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February 18, 2015
Crowdfunding in Mongolia
Санхүүжүүлэлт болон хѳрѳнгѳ оруулалтын орчин сүүлийн үед их ѳѳрчлѳгдѳж байна. Текнологын шинэчлэлийг даган энэ салбар...
useful stuff to know
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mongolmonster Media
Spain's central government debt is at 593 Billion Euro. Euro zone needs more money to bail both Spain and Italy.
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Mongolia is a boom country on the frontier of global mining.Only 25% of the country has been geologically surveyed and already many world class deposits identified and in various stages of development and production.
More than 80% of its exports are minerals, a proportion expected to rise in a few years to 95%. Mongolia makes mining geologists salivate over its known riches and unexplored potential—for copper, coal, gold, silver, uranium, molybdenum, and on and on. Some 3,000 mining licences have been issued.
Oyu Tolgoi
Oyu Tolgoi is the world's largest undeveloped copper-gold project and is located in the South Gobi region of Mongolia, approximately 550 km south of the capital, Ulaanbaatar, and 80 km north of the Mongolia-China border.
The mine produced 1 million metric tons of coal last year and is expected to produce 3 million-4 million tons this year. Production will likely rise to 7 million tons next year and 20 million tons by 2015-2017, Mr. Igata said.
The Tavan Tolgoi coal mine in Mongolia's southern Gobi region has estimated reserves of as much as 7.5 billion tons of coal, including the world's largest deposit of coking coal, a steelmaking material.
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AFRAN is one of four Regional Networks on Ageing organised and supported by the OIA.
Through running AFRAN the OIA
- Provides a platform for exchange and capacity building between network members
- Forges collaborative research and training initiatives undertaken by AFRAN members in partnership with the OIA
In developing research and capacity building programmes AFRAN draws on directions and approaches identified by the strategic plan and framework for research on ageing in sub-Saharan Africa that was developed as an outcome of the April 2005 Oxford Conference on Research on Ageing in Africa.
AFRAN is coordinated by Dr. Jaco Hoffman who leads the Africa Programme at the Institute of Population Ageing University of Oxford.
The network is guided by a 8-member advisory board comprising African scholars and civil society representatives. In addition, AFRAN draws on strategic consultation with a group of International Advisors representing key research and policy bodies.
If you wish to join as an organisation, please download and complete this form.
Current AFRAN members include Africa-based individual and institutional members, as well as members from European and international research institutions. For details on current members click here
Membership to AFRAN is open for anyone engaged or interested in research on ageing issues in African populations. To become a member of AFRAN please contact us
If you wish to join as an individual, please downlaod and complete this form.

subset: commoncrawl


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I currently use Adminimize but today I have a weird bug.
I can not desactivate the options that I've checked before.
All checkboxs are unchecked but an Editor User still not see all the parts that were hidden before (plugins, cpt, themes). The Tools menu reappear but no submenu inside.
I've tried :
- to reset by the option you give at the end of the adminimize configuration page
- delete manually the option in wp_options table
- empty cache
Nothing seems to work for me. Does anyone have an idea of what I miss ?


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Post your Comment
Business Performance management
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Paprika Chicken
23 Dec 2009
Paprika Chicken is a terrific spicy chicken with creamy gravy that you will love to have with pasta. Enjoy this as a casual or party meal with family and friends. Come back here and express what you think about this Paprika Chicken.
|Broiler fryer chicken
|4 Pound, cut up (1 Piece)
|Cooking oil
|1 Tablespoon
|1 Tablespoon
|Sliced fresh mushrooms
|1 Cup (16 tbs)
|Diced onion
|1 Cup (16 tbs)
|Diced green pepper
|1 Cup (16 tbs)
|Diced sweet red pepper
|1 Cup (16 tbs)
|All purpose flour
|3 Tablespoon
|Canned chicken broth
|14 1⁄2 Ounce (1 Can)
|Tomato paste
|1 Tablespoon
|1 Tablespoon
|1 1⁄2 Teaspoon
|1⁄2 Teaspoon
|Hot cooked noodles
|1⁄2 Cup (8 tbs)
|Sour cream
|1⁄4 Cup (4 tbs)
In a Dutch oven over medium heat, brown chicken in oil and butter; remove chicken.
Discard all but 3 tablespoons drippings.
Saute mushrooms, onion and peppers in the drippings until crisp-tender, about 2-3 minutes.
Stir in the flour until smooth.
Gradually add broth, stirring constantly.
Bring to a boil; cook and stir for 1 minute or until thickened.
Stir in tomato paste, paprika, salt and pepper.
Return chicken to pan; bring to a boil.
Reduce heat; cover and simmer for 60-70 minutes or until chicken juices run clear.
Remove chicken to a platter of noodles; keep warm.
Add sour cream to sauce; stir until smooth (do not boil).
Spoon over chicken and noodles.
Recipe Summary
Difficulty Level:Easy
Course:Side Dish
Rate It
0 Comments
Paprika Chicken Recipe


text: I'm not much of a photographer, but I'm working on it, improving. I like objects as subjects, rather than people; close-ups, rather than faraway angles. Twice a week or so I find a sunny spot, get some of my possessions into the light, and take pictures. Amateur? I don't deny it -- but photography is fun.


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Originally posted by nake13
reply to post by NarcolepticBuddha
I also found 2001 to be a deeply thought provoking movie,and the special effects still stand the test of time.However,my all time fravourite movie for the big screen is Bladerunner,based on Phillip K Dick's "Do androids dream of electric sheep",I find Dick's writing to be the most beautiful experience that I have had(of the printed word anyway!) and to me bladerunner perfectly captured the essence of Dick's short story completely.
Originally posted by Chukkles
The way you describe it NB, makes me want to see it.
I never have BTW.
Originally posted by Chukkles
I've bookmarked the full film in 2 parts from metacafe.com.
Will be watching it soon.
Originally posted by raypsi13
the book explains alot you can't figure out in the movie.


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Get dining news including restaurant closures and qualify for giveaways.
Ouisi Bistro is Vancouver's orignal New Orleans restaurant, serving up authentic cajun and creole cuisine.
Came here for Saturday brunch. The eggs benny was disappointing, luke warm and eggs were over done. The sides were disappointing - hash brown potatoes were not hot and the fruit salad looked like it came straight from a can. The bread they use for french toast was thin - prefer thicker texas toast
I have been here for dinner service and the food is so much better - perhaps they have different chefs?
Bottom line is there are better choices in the South Granville Neighbourhood for brunch like Luke's or Heirloom
Hubby and I were doing some early Christmas shopping on the Granville Rise. Feeling peckish, and passing by, we read the menu outside and thought we would try Ouisi.
Hubby ordered a chorizo, potato and sausage hash, which he said was quite tasty. Coffee, however, was weak and not very hot. Refills were hard to come by...
I ordered "Egg Me On", one poached egg, cheddar cheese, tomatoes, cucumbers, sprouts and toast. The egg was good, but lukewarm. Everything else, including the toast, was cold and lumped in separate piles on the plate.
I asked (Itwice) or orange pekoe tea, and got a mug of hot water and a tea bag. No milk, no offer of milk.
Service was perfunctory at best. Middle-aged shoppers were not cool enough, apparently, for any interest. I really don't really care how many facial piercings you have, honey, if I'm spending my money, I expect some effort on your part.
Won't return to be invisible again. For not very good food.
For the longest time, I've been meaning to give their menu a try. Only just recently gotten around to doing so for a late dinner. I thought the service was adequate, though unenthusiastic, while my dining partner felt it was cold & bordering on neglect. Food preparation is relatively slow. Complimentary cornbread was decently moist, though it comes with an obviously prepackaged rectangle of unsoftened butter for a boring spread, but that's about standard for general offerings elsewhere.
The 3 course tasting menu doesn't provide value, but it does provide a less than satisfactory dining experience. The Jambalaya is just typical seafood drenched in a tomato sauce that tastes of the instant/canned variety--my dining companion actually felt it was like sauce masking cardboard, but I wouldn't go so far as to call it such. I wouldn't recommend anything that comes with their fragranted rice as neither the green nor the regular variety is any good. As a matter of fact, they offer an odd taste and is a bit too mushy resembling the instant Uncle Ben's microwave variety. The gumbo variety is awful in its heavily salted black sauce. Maybe you shouldn't be going here for the New Orleans/Creole cuisine, but rather, the simply baked/grilled chicken and such dishes might be a safer bet. I would also not recommend getting any of the desserts offered with the tasting menu.
My wife and I came here last night for a couple's Supper Club Night. The restaurant is small, dark and funky. The wall hangings have lots of reference to jazz and New Orleans.
I started off with the cornbread and butter basket and my wife had the baby spinach salad with vinaigrette and blue cheese. The cornbread is one of the best I've ever had. Not too sweet, and not too gritty, it was moist yet also crumbly in texture. My wife finished her salad, so it must have been okay.
I had the Apricot Expresso Brandy glazed 1/2 chicken with steam veggies and a cornbread/andouille sausage stuffing with smoked corn sauce. One of the better meals that I have had dining out. chicken was moist and flavourful...didn't really taste the expresso though. The stuffing was outstanding with the most conbread and spicy fried cubes of andouille sausage. Smoked corn sauce was really good too, just a bit oily for my taste though.
My wife had the Voodoo Ribs with potatoes and veggies. She said her ribs were falling off the bone and were excellent.
Service was good, not great. My water was refilled 3 times withouth me having to ask for it. My wie shared a bottle of wine with 2 other people sitting at our table.
After tax and tip (which for most parties over 6 people, an automatic 16% gratuity is added), it came to $84 for the both of us. I just wish that the waitress told me that before I almost added another 15% tip on top of the bill...fortunately for me, I caught it stated at the bottom of the receipt
Would I go again, probably, if I was in the area.
I really don't have much to say about the food as it doesn't stand out. The food is just OK, but it's consistent although it never seems to be warm enough.
However, the service is not as consistent as the food. The service is more or less decent, but somewhat amateurish. During one dinner my server had a bit of a flippant attitude and just did what he was supposed to without really caring. At one point he spilled a full beer on me. I watched the whole fiasco play out in slow motion. The server went to put the beer on the table, but wasn't paying attention to where he was setting it down as he was scanning the room instead. He ended up placing the beer on a knife and the whole thing tipped over and spilled into my lap. He brought a cloth over for me, but it was ineffective as even my underwear was soaked.
I understand that accidents happen, but the server's subsequent actions were very disappointing. He didn't bring any dessert or whatever to make it up to me and he didn't comp anything on the meal either. The least he could have done was offered me a free dessert for soaking my pants in beer. His carelessness ended my evening there as I had to go home and miss the movie premier I had passes to. I lived too faraway to go home and change and make it to the theatre so the evening was a write off.
I went back to Ouisi last night and wasn't entirely "wowed". My friend tried the House Flight which was a sampler dish and if you've never had Gater before you can at least say you've tried it (not for me) I found the menu a bit lacking in variety, and a bit pricey. The ambiance is unique though.
We went once for a dinner for two and it was good enough to go back and try out more dishes. The second time I tried a chicken dish but it didn't settle well with me. It could have been the spices, but i like hot stuff! We were mostly ignored and I felt like we just had to leave the place. I'm not ugly or anything but I felt like it. I have heard not very good things about this place from others. I think that's why they did the renovations and I haven't been back since. Mebbe it's changed?
I hope someone writes something good so I can think about giving it another try. sigh!
We were looking forward to trying this restaurant. We were greeted nicely and seated and then forgotten about for the rest of our time there. No one greeted us at the table and we had to flag down someone to order drinks and our meal. It wasn't that busy either. The food was pretty good but the bad service made the whole experience unpleasant.
Took my lovely wife out for her fiftyth birthday celebration. She picked Ouisi's for a change of pace. Drove in from Port Moody. Nice place, interesting ambiance. The food was pretty good. We had a couple of appy's. Liked the 'gator best! The main dishes were ok to great. Two people had jambalya which were definately mediocre. Two people had Po'boys which I think were good. I had the Chicken and Duck Sausage Gumbo, it was great! I would definately eat that again. So why the mediocre rating? My wife ordered a New Orleans Fizz to start out the night. She made quite the face when she took a sip and offered me a taste. Yuck! Tasted like soap! Passed it around and everyone agreed it was nasty. When the server checked in we mentioned the taste and sent the drink back. Turns out the simple syrup container had been filled with liquid soap! Blech! I understand this could happen to anyone but what I didn't like was no apology from management and I had to ask if they were comp-ing the drink. They were but nothing else was done. When I'm fed soap I would appreciate a little better treatment than that.
i heard a lot about this place and finally had a chance to dine there. it was not a let down.
Gator Bites ($14)
- very tasty, tough meat, but i think that's because its reptile. very well seasoned. i could've had it for an entree, with some sides.
Portabello Mushroom ($11)
- relative to the gator, a bit underwhelming and for one mushroom it was pricy.
Creole Beef ($18)
- sides were assorted veggies and mashed potato.
- great mashed potato, but its hard to screw up that dish.
- the actual beef tips was tender and tasty as well. however its not so different from a couple of asian fusion restaurants i've been to. price for the dish was average and comparable to similar dishes in other places.
Southern Fried Catfish ($23)
- i didnt order this one but had a bite to taste
- same sides as the beef i think
- it tasted ok, but the texture was almost creamy, but maybe its the fish, or i'm just not used to catfish. i've tried the sable fish at a couple different places and thats my standard for judging fish dishes now. and its a bit let down from the catfish. $23 also seemed a bit steep for the quality.
Vanilla gelato (3.75)
- typical
overall, i think its a good place to frequent. not sure about authenticity as i've never had "real" creole/cajun food from down south. i would definitely go back for more of those gator bites.
We went out tonight to Ouisi for dinner as we do every couple of months. When reviewing their menu we noticied that they have made some changes. There are new items on the menu and they have added that you can choose 2 sides with your main dish. There were approx. 10 sides to choose from. AND they have brought back the comp. corn bread with the meal. My husband ordered the southern fried chicken with smoked cream corn and beets. I ordered the gulf prawns with yummy diablo sauce. There is a choice of 2 different sauces. The diablo is a mixture of BBQ & hot sauce. For my 2 sides I had the coleslaw and sweet potato/peacan hash. Our meals were excellent!!! The chicken was very lightly breaded with a tasty sauce and the were 10 sizeable prawns with ample sauce. The sides were in a dish that I would call a cup. They were all great too. The cost was reasonable. The chicken was $17.00 the prawns were $16.00. Great valueand quality for what we paid. We had the same friendly server that we have had in the past. The only problem was the guy at the table next to us who loved to hear his own voice. We will be back soon in the near future.
The cornbread tasted old – you can taste the difference between cornbread that is fresh out of the oven and cornbread that has been sitting for the whole day. I ordered the Corncrusted Trout with Mango Chipotle. The fish was dry and tasteless, not impressed at all for $18. A friend ordered the Jambalaya but it was WAY too spicy for anyone to enjoy. When we asked her if it was supposed to be that spicy, she said that "it may have been from a different batch" which screams inconsistency. I probably won't return.
It is always a pleasure going to ouisi. I have always been impressed the decor (paintings bylocal artists and always new ones everytime we go). The food is standard Louisiana/Jamaican fare, and there is always just enough spice on everything (try the hot sauce on the table if you are brave). The only complaint (not really one) is that the alligator meat tastes like dried lizard (but I think that's because of the meat not the cooking). It's one of the most enjoyable dining experience I had in Vancouver.
We hit Ouisi Bistro after stuffing ourselves at Shabusen for drinks and a good time. A few people ordered food, but there weren't rave reviews. Pick a nice night in the summer and make sure you sit out back. You wouldn't expect that Ambiance at the back of a granville street restaurant.
We were moved inside after 12, as the neighbor (apparently a crotchity old woman) complains whenever there's a slight noise. Not a big deal though and the party continued for longer.
The service and the rest of the staff were good. No complaints about that.
The food, however, was awful. I took a friend who had recently returned from New Orleans for a dinner hoping it would remind her of her trip. I asked her honest opinion of the food and she said it's nothing like the "real thing." That's fine... you can't expect it to taste exactly the same. In general though, the taste was just bad. The Gumbo might as well have been straight out of a Chunky Soup can. The Jambalaya might as well have been an Uncle Ben's recipe. The tasted like it was cooked in Campbell's tomato soup with a dash of safeway Cajun spice mix. The muffuletta was basically just a small ham and cheese sandwich with some olive relish in it... at least it was edible.
The decor was nice, but the music was too loud for my liking. And it was empty... on a friday night.
I will not return.
Went with hubby near the end of October to use up our Entertainment Book coupon before it expired.
Food: We lucked out because it was the last day of their week-long gumbo festival. The warming and filling gumbo stew (served over rice) was perfect for a chilly evening. I had the seafood one, which came with 2 plump fried oysters, 6 large mussels, a few medium scallops and some prawns - beautiful presentation. Hubby had the lamb gumbo. Both were good, although I preferred mine (especially after I added the hot sauce). They also went well with the side of corn bread we ordered. For dessert, we shared the pecan pie, which came with a yummy bourbon sauce.
Service: I'd give the lone waitress 4 stars (very friendly and checked on our food), but the restaurant 3 stars as it should have had 2 wait staff that night as it made service slower than it could have been.
Value: Unlike some other restaurants, they let us use our entertainment coupon for the gumbo specials (both $18 - so reasonable value even without the coupon). The pecan pie was huge (easily the size of 2 pieces at other places) - and costs less than $6 (I think it's $5.45)! The 4-piece cornbread side was only $2.50, and hubby's lemonade was only around $2.
Ambiance: Not bad. Had some nice local paintings on the wall. It was a bit dark for my liking, though.
All in all, worth a repeat visit.
I tried this place for the first time on wednesday and had their dine out menu. The portions were very large, unlike some other places during dine out. The smoked gouda and bacon salas was the best salad I have ever eaten! I had the Southern fried chicken breast as my entree and it was sooooo flavourful. My friend had the Jambalaya, whcih she said was exceptional. The pecan pie was not the best i have ever had, but overall the food was great, the atmosphere was nice but service was quite slow. It took quite a while for the waitress to take our drink or dinner order, but once the food came out, they were pretty quick between courses. i would definately go there again and try out some more of their menu.
I ate at the Ouisi Bistro last night and had a great time. The server was friendly and attentive but didn't bother us like they do at some placesdo when they hover around. I wasn't sure what to order and was recommended the espresso half chicken. It was fantastic! Too big though so I had it wrapped to go. My girlfriend had a peppered chicken that she said was incredible (how can something covered in brie not be good though?) What I really liked though was that when we asked for a recomended wine, our server suggested a pinot noir that wasn't over the top in price. So many places suggest the most expensive items to get you to spend more. We had a great time and will definitly go back!
My best friend ordered the Roasted Vegetable Cheesecake and I ordered some chicken dish - I had a bite of hers and I ended up eating her whole dish! My other friend ordered the jambalaya, and I ended up eating a good part of her dish too. Now I'm a happy cow, but I'm down two friends.
We were told 15-20 minutes for a table, but it was actually much longer than that. The waiters and waitresses never checked on us and didn't give us water.
My husband and I had a craving for Creole food after our trip to New Orleans last year, so we decided to try the Ouisi Bistro last Saturday. We were not disappointed, We absolutely LOVED the food, the ambiance and the overall atmosphere, it very much reminded us of some of the places we visited in the French Quarter.
On the recommendation of our terrific server, a very charming young man, we decided to try a selection of different things and were so glad we did!. We loved the crab cakes and gator bites, the Baton Rouge greens and frites were delicious and the corn bread to die for and we both thoroughly enjoyed the Jambalaya.
Having such a terrific server was wonderful, and added so much to our evening's enjoyment. At so many places, we have felt either ignored or fussed over too much. We dine our regularly and good service is very important to us, so although the place was very busy he bent over backwards to make our experience a memorable one and was always attentive without being overbearing. Just the way we like it!. His knowledge of wine was most impressive too and his suggestion to us was spot on!
We will most certainly be going back and I believe every other Thursday they have live Jazz so that is something we shall aim for.
|Bump N Grind (9 m)
|SalonTea (12 m)
|Meinhardt Fine Foods (21 m)
|Phoscao Cafe (40 m)
|Luke's Corner Kitchen & Bar (56 m)
|Kyo Korean BBQ & Sushi House (70 m)
|Bean Around The World (82 m)
|Caffe Barney (83 m)
|Pho Hoa (103 m)
|Stable House Bistro, The (139 m)


text:
I am very, very excited to post my second self-authored and illustrated children's book, The Summer Zoolympics. This is a mock-up I made (the sole copy), but I'm looking for a publisher. Fingers crossed. :)
More info. here.
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Hey cat owners.....
Joleen + Chad = Dominic Mason (10/25/06), Jaxon Jesse (2/25/13), Greyson Travis (3/6/15), & BABY GIRL due May 16th, 2016
Nope. Mine is totally freaked out by my magical moving baby bump. He's usually very cuddly too.
This was them over the summer:
Mine doesn't but that's because shes my roommates and we just got her from an abusive home. (although she has claimed me) But I was raised with cats and keep in mind they love your bump because 1: its warm and 2: its round. lol Cats are funny, but these are their favorite things! They probably also enjoy the relaxing sound of the heart beat, and most likely know there is a cute baby in there. (they know these things!)
Our Rainbow baby was born March 6, 2013 at 8lb 5oz and 21in long.
It's not a waddle, it's my penguin swagger.


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Douse Lights At Night
We've been taking a class taught by Dr. Shanil Verani at James Madison University's planetarium. On March 10, his special guest was Paul Bogard of the English Department, who has written, "The End…
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Greetings from Lawrence, Kansas! For a festival that hasn't even officially started yet, Thursday evening was jam packed. STS9 had to cancel their appearance at the last minute due to unfortunate circumstances and so Umphrey's McGee was granted an extra set. They played for four hours with a short set break and it was your "typical" triUMPHant and frenetic "improg" show and a great way to kick off the festival in high gear. Brendan Bayliss let everyone know that "Wakarusa" means "ass deep" - the original meaning of the word likely to describe the river but we'll no doubt use many times over the weekend. Aron Magner and Marc Brownstein (of The Disco Biscuits at Wakarusa with Conspirator who will perform tomorrow late night) sat in for a sweet electro-metal jam that was chock full-o-flava. Already the Wakarusa vibe is starting to set in...
The Cajun blues rock of Papa Mali sent us off into the Kansas night. We've got TONS more music to see this weekend. We're also looking forward to seeing the beautiful Clinton State Park during the daylight hours. Stay tuned and we'll keep you posted on what's happening here at Wakarusa. It's all happening!
Words by: SuperDee
Images by: John Smrtic
JamBase | Wakarusa
Go See Live Music!


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Visceral white adipose tissue (WAT) hypertrophy, adipokine production, inflammation and fibrosis are strongly associated with obesity, but the time-course of these changes in-vivo are not fully understood. Therefore, the aim of this study was to establish the time-course of changes in adipocyte morphology, adipokines and the global transcriptional landscape in visceral WAT during the development of diet-induced obesity.
C57BL/6 J mice were fed a high-fat diet (HFD) or normal diet (ND) and sacrificed at 8 time-points over 24 weeks. Excessive fat accumulation was evident in visceral WAT depots (Epidydimal, Perirenal, Retroperitoneum, Mesentery) after 2–4 weeks. Fibrillar collagen accumulation was evident in epidydimal adipocytes at 24 weeks. Plasma adipokines, leptin, resistin and adipsin, increased early and time-dependently, while adiponectin decreased late after 20 weeks. Only plasma leptin and adiponectin levels were associated with their respective mRNA levels in visceral WAT. Time-course microarrays revealed early and sustained activation of the immune transcriptome in epididymal and mesenteric depots. Up-regulated inflammatory genes included pro-inflammatory cytokines, chemokines (Tnf, Il1rn, Saa3, Emr1, Adam8, Itgam, Ccl2, 3, 4, 6, 7 and 9) and their upstream signalling pathway genes (multiple Toll-like receptors, Irf5 and Cd14). Early changes also occurred in fibrosis, extracellular matrix, collagen and cathepsin related-genes, but histological fibrosis was only visible in the later stages.
In diet-induced obesity, early activation of TLR-mediated inflammatory signalling cascades by CD antigen genes, leads to increased expression of pro-inflammatory cytokines and chemokines, resulting in chronic low-grade inflammation. Early changes in collagen genes may trigger the accumulation of ECM components, promoting fibrosis in the later stages of diet-induced obesity. New therapeutic approaches targeting visceral adipose tissue genes altered early by HFD feeding may help ameliorate the deleterious effects of diet-induced obesity.
Keywords:Adipocytokine dysregulation; Transcriptional response; Adipose tissue; Extracellular matrix; Cathepsin; Fibrosis
White adipose tissue (WAT) not only serves as a fuel storage depot but also releases a variety of bioactive factors, called adipokines, which have pro-and anti-inflammatory activity. In obesity, most adipokines, including leptin, resistin and tumor necrosis factor alpha (TNFα), are overproduced and promote inflammation. Whereas, the production of anti-inflammatory adipokines, such as adiponectin, is decreased with increasing adiposity. Since, inflammation is considered to be causal in the development of obesity and insulin resistance [1-3], the dysregulated production of adipokines caused by excessive adipose tissue expansion is linked to the pathophysiology of obesity-related metabolic syndrome [4].
There is a close relationship between inflammation and the extracellular matrix (ECM), which requires remodelling to accommodate adipocyte growth during adipose tissue expansion. In obesity, adipose tissue inflammation is further exacerbated by excessive accumulation of ECM components in adipose tissue, possibly as a result of pro-inflammatory cytokines released by adipocytes [5]. Excessive accumulation of ECM components may represent a key event in obesity-mediated adipose tissue fibrosis, similar to fibrosis in other tissues such as liver [6,7]. Acumulating evidence indicates that altered circulating adipokine levels contribute to the progression of cardiac or hepatic fibrosis [8,9]. Thus, adipokine dysregulation may also regulate remodeling of the adipocyte ECM and fibrosis. However, the actual time-course of adipokine dysregulation, inflammation, ECM accumulation leading to the development of adipose tissue fibrosis is yet to be fully established.
High-throughput microarrays assessing global gene expression changes provide a unique window into the molecular events occurring in adipose tissue during the development of obesity. Previous microarray studies have revealed that a high fat diet (HFD) is associated with adipokine dysregulation, inflammation and fibrosis [10-15]. However, these microarray studies tend to compare gene expression differences at a single end-point only or over short-time periods between 2–12 weeks. Following the molecular changes in adipose tissue during the development of obesity in humans is not feasible. Therefore, time-course models of diet-induced obesity in mice can help improve our understanding of the molecular pathogenesis of obesity in-vivo. However, the use of genetically obese animals or extremely high levels of dietary fat intake, which do not reflect normal dietary consumption hampers the translation of findings from mouse obesity models to humans [10-14]. Therefore we established a long-term diet-induced obesity model, by feeding C57BL/6 J mice with a high-fat diet (39%kcal) or normal diet for 24 weeks and sacrificing mice at regular time-points to allow in-depth time-course microarray analysis of visceral adipose tissue depots.
Accordingly the aim of the present study was to establish the time-course of changes in adipocyte morphology, adipokines and the global transcriptional landscape in visceral adipose tissue depots during the transition from a lean to obese phenotype in HFD fed mice. We primarily focus on the timing of changes associated with adipokine levels, inflammation and fibrosis, which are recognized as important factors associated with human obesity.
Three hundred and sixty male inbred C57BL/6 J mice were obtained from the Jackson Laboratory (Bar Harbor, ME) at 4 weeks of age. All the mice were individually housed under a constant temperature (24°C) and 12-hour light/dark cycle, fed the AIN-76 semi-purified diet for one week acclimation period after arrival, and then randomly divided into a normal diet (ND) and an HFD group, with 18 mice per group for 0, 2, 4, 6, 8, 12, 16, 20 and 24 weeks. After the acclimation, the HFD group was fed the AIN-76 semi-purified diet with 39.2 kcal% fat (American Institute of Nutrition, 1977) consisting of 20% fat and 1% cholesterol ( Additional file 1: Table S1). Every 2–4 weeks, after a 12 h fast, blood samples were drawn from the inferior vena cava. Blood was collected in heparin-coated tubes, centrifuged at 1,000 × g for 15 min at 4°C and then stored at −70°C. Mice were anaesthetized and sacrificed at 0, 2, 4, 6, 8, 12, 16, 20 and 24 weeks. The adipose tissues were then removed, rinsed, weighed, immediately frozen in liquid nitrogen, and stored at −70°C until further analysis. The current study protocol was approved by the Ethics Committee for animal studies at Kyungpook National University, Republic of Korea.
Additional file 1. Table S1.Composition of experimental diets. 1AIN-76 mineral mixture (grams/kg): calcium phosphate 500, sodium chloride 74, potassium citrate 2220, potassium sulfate 52, magnesium oxide 24, magnesium carbonate 3.5, ferric citrate 6, zinc carbonate 1.6, cupric carbonate 0.3, potassium iodate 0.01, sodium celenite 0.01, chromium potassium sulfate 0.55, sucrose 118.03, 2AIN-76 vitamin mixture (grams/kg): thiamin HCL 0.6, riboflavin 0.6, pyridoxin HCL 0.7, niacin 3, calcium pantothenate 1.6, folic acid 0.2, biotin 0.02, vit B12 1, vit A(500,000U/gm) 0.8, vit D3(400,000U/gm) 0.25, vit E acetate(500 U/gm) 10, menadione sodium bisulfite 0.08, sucrose 981.15, ND: normal diet (AIN-76), HFD: high-fat diet (20% fat, 1% cholesterol)
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Plasma adipokines
Radioimmunometric assays were performed for the measurement of plasma amylin (amylin RIA kit; Diagnostic Systems Laboratories), adipsin (adipsin RIA kit; PerkinElmer Life and Analytical Sciences, Boston, MA), adiponectin (adiponectin RIA kit; PerkinElmer Life and Analytical Sciences, Boston, MA), leptin (Mouse leptin RIA kit; Linco Research, St. Charles, MO), and resistin concentrations (resistin RIA kit; PerkinElmer Life and Analytical Sciences, Boston, MA).
Morphology of fat tissues
Epididymal adipose tissue was fixed in 10% (v/v) paraformaldehyde/PBS and embedded in paraffin for staining with hematoxylin and eosin (H&E) and Masson's trichrome. The stained area was viewed using a microscope at a magnification of 200× and 400×, respectively.
RNA preparation and quality control
Total RNA was extracted from the adipose tissue using TRIZOL reagent (Invitrogen Life Technologies, Grand Island, NY) according to the manufacturer's instructions. DNase digestion was used to remove any DNA contamination and RNA was re-precipitated in ethanol to ensure no phenol contamination. For quality control, RNA purity and integrity were evaluated using the Agilent 2100 Bioanalyzer (Agilent Technologies, Palo Alto, USA). For epididymal adipose tissue, six pooled RNA sample sets were constructed for the ND and HFD groups at each time-point as described previously [16]. In mesenteric adipose tissue, one pooled RNA sample set was constructed for the ND and HFD groups at each time-point based on 18 individual samples. RNA was stored at −70°C prior to further analysis by microarray and RT-qPCR.
Microarray analysis
Total RNA was amplified and purified using the Ambion Illumina RNA amplification kit (Ambion, Austin, USA) to yield biotinylated cRNA according to the manufacturer's instructions. After purification, the cRNA was quantified using the ND-1000 Spectrophotometer (NanoDrop, Wilmington, USA). 750 ng of labelled cRNA samples were hybridized to each Illumina MouseWG-6 v2 Expression BeadChip for 16–18 h at 58°C, according to the manufacturer's instructions (Illumina, Inc., San Diego, USA). Detection of array signal was carried out using Amersham fluorolink streptavidin-Cy3 (GE Healthcare Bio-Sciences, Little Chalfont, UK) following the bead array manual. The quality of hybridization and overall chip performance were monitored by visual inspection of both internal quality controls and the raw scanned data. Raw data was extracted using the Illumina BeadStudio software provided by the manufacturer. Probe signal intensities significantly higher than background intensities were determined (detection p-value > 0.05), but probe signal data were not filtered to preserve probes with low expression at different time points. Probe signal intensities were quantile normalized and log transformed. Microarray analysis was performed in ArrayAssist (Stratagene, USA), Bioconductor and R programing language. LIMMA was used to determine significant differentially expressed genes (HFD responsive genes) between HFD- and ND-fed mice at each time point based on FDR < 5%, Benjamin and Hochberg adjusted p-value <0.05 and log fold change >1 [17]. This microarray data was deposited in Gene Expression Omnibus (GEO) database (GEO accession numbers: GSE39549).
The same total RNA (1 μg) samples that were hybridised to microarrays were reverse-transcribed into cDNA using the QuantiTect® reverse transcription kit (Qiagen, Germany). Then mRNA expression was quantified by real-time quantitative PCR, using the SYBR green PCR kit (Qiagen, Germany) and the CFX96TM real-time system (BIO-RAD). Gene specific mouse primers were used to detect leptin, adiponectin and resistin (Additional file 2: Table S2). Cycle thresholds were determined based on SYBR green emission intensity during the exponential phase. Ct data were normalized using Gapdh, which was stably expressed in both HFD and ND fed mice. Relative gene expression was calculated using the 2−△△Ct method [18].
Additional file 2. Table S2.Primer sequences used for RT-qPCR validation of microarray data.
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Functional features of high-fat feeding responsive genes in visceral adipose tissues
To identify which biological processes were associated with the visceral adipose tissue genes altered by HFD at one or more time-points over 24 weeks, enriched functional features were identified using DAVID [19]. The analysis was performed using Gene Ontology and Pathways and mapped by DAVID ID. Then the DAVID Functional Annotation Clustering tool [19] was applied to identify enriched biological themes and cluster redundant annotation terms.
Identification of genes that respond to both age and high-fat diet simultaneously in epididymal adipose tissue
Next, we examined which HFD-responsive genes in epididymal adipose tissue were correlated with age and/or body mass. At first, genes affected by advancing age were identified by examining genes that were continuously up- or down-regulated in the both ND and HFD group. These genes were overlaid with the HFD-responsive genes (HFD vs. ND, fold change > 2 and p-value < 0.05) to screen genes that responded to both age and high-fat diet simultaneously in epididymal adipose tissue. These overlapped genes were selected and correlated with body mass.
Statistical analysis
The parameter values were expressed as the mean (standard error of the mean (SEM). Significant differences between groups were determined by student's t-test and wilcoxon t-test using the SPSS program (SPSS Inc., Chicago, IL). Correlation analyses utilized the Pearson's coefficient. Results were considered statistically significant at p < 0.05.
Time-course of changes in body weight and food efficiency during diet-induced obesity
Significant increases of body weight gain and energy consumption were observed in the HFD group after the 4th week and 2th week, respectively. The food efficiency ratio (FER) was also significantly increased in the HFD group after the 4th week of high-fat feeding (Additional file 3:Table S3) [20] compared to the ND group.
Additional file 3. Table S3.Body weight gain, food intake and food efficiency in C57BL/6 J mice fed the different diets for 24 weeks. Data shown as means ± S.D. Values are significantly different from the ND group according to Student's t-test: *p < 0.05, **p < 0.01, ***p < 0.001. ND: normal diet (AIN-76), HFD: high-fat diet (20% fat, 1% cholesterol), FER: food efficiency ratio.
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Time-course of changes in WAT depot weights, adipocyte size and adipose tissue fibrosis during diet-induced obesity
When WAT weights were expressed in g/100 g WAT, visceral WAT depots including epididymal, perirenal, retroperitoneum, mesentery WAT were significantly increased from week 2 in the HFD group compared to ND group. Similarly, from week 2, subcutaneous WAT was significantly higher in the HFD group (Figure 1). In addition to increased body fat, adipocyte size was also enlarged in the epididymal WAT depot in a time-dependent manner (Figure 2A).
Figure 1. Timely effect of high-fat feeding on adipose tissue weights over 24 weeks in C57BL/6 J mice. Data shown as means ± S.D. Values are significantly different from the ND group according to Student's test: *p < 0.05, **p < 0.01, ***p < 0.001. ND: normal diet (AIN-76), HFD: high-fat diet (20% fat, 1% cholesterol), WAT: white adipose tissue.
Figure 2. Timely effect of high-fat feeding over 24 weeks on (A) H&E and (B) Masson's trichrome staining of epididymal white adipose tissue in C57BL/6 J mice. (A) H&E stained transverse-section of epidydimal fat. Original magnification × 200. (B) Masson's trichrome stained transverse-section of epidydimal fat. Fibrillar collagens, primarily collagen I and III, are stained with blue as indicated with arrowheads. Nuclei and keratin are stained with deep purple and red, respectively. Original magnification × 400. ND: normal diet (AIN-76), HFD: high-fat diet (20% fat, 1% cholesterol).
To assess fibrosis Masson's trichrome staining was performed, which revealed the epididymal WAT depot of the HFD group contained very pronounced trichrome-positive "streaks" interspersed among the adipocytes at 24 weeks. Whereas, the epididymal WAT depot of the ND group revealed a normal fat-pad, with densely packed and very thin collagen sheets surrounding each adipocyte at week 24 (Figure 2B).
Time-course of changes in plasma adipokine, glucose, insulin and lipids levels during diet-induced obesity
The time-course of changes in plasma adipokine levels in response to HFD is shown in Figure 3. The most prominent changes were observed in leptin and resistin levels, which were increased from week 4 to week 24 in the HFD group. Plasma adipsin levels were also elevated in the HFD group from week 4, reaching a peak at week 6 and thereafter gradually decreasing. In contrast, plasma adiponectin levels in the HFD group tended to be lower than in the ND group for the overall feeding period and were significantly lower at week 20 and 24. Fasting blood glucose and insulin resistance and plasma total cholesterol concentration were markedly elevated in the HFD group after 16 week and 6 weeks, respectively. No differences in plasma TG and FFA levels were detectable between the HFD group and ND group at any time points (data not shown) [21].
Figure 3. Time-resolving effect of high-fat feeding over 24 weeks on plasma concentration of (A) leptin, (B) resistin, (C) adiponectin and (D) adipsin in C57BL/6 J mice. Data shown as means ± S.D. Values are significantly different from the ND group according to Student's test: *p < 0.05, **p < 0.01, ***p < 0.001. ND: normal diet (AIN-76), HFD: high-fat diet (20% fat, 1% cholesterol).
Time-course of transcriptional changes in epididymal and mesenteric WAT depots during diet-induced obesity
In the epididymal WAT depot, 2037 genes were altered at one or more time points in response to HFD intake over 24 weeks (Table 1), of which 1610 genes were up-regulated and 445 genes were down-regulated. In mesenteric WAT depot, 1784 genes were altered at one or more time point in response to HFD intake over 24 weeks, of which 1134 genes were up-regulated and 892 genes were down-regulated (Table 1). Functional gene ontology terms associated with these HFD responsive genes in the epididymal WAT and mesenteric WAT depots were clustered using DAVID (Table 2). Immune and inflammatory system function terms were enriched among the consistently up-regulated genes across all time-points, in response to HFD, in both the epididymal and mesenteric WAT depots (Table 2A). Glucose metabolic system function terms were enriched among the down-regulated genes (Table 2B). Lipid and cholesterol metabolism related functional gene ontology terms were specifically enriched among the down-regulated genes in the mesenteric WAT depot across all time-points.
Table 1. Number of high-fat diet responsive genes in two visceral WAT depots at multiple time-points in C67BL/6 J mice
Table 2. Functional annotation gene clusters (A) up-regulated and (B) down-regulated in visceral adipose tissue depots by high-fat feeding in C57BL/6 J mice over 24 weeks
Epididymal WAT depot genes altered by advancing age and diet-induced obesity
When HFD-responsive genes, in epididymal WAT, were overlapped with age-dependent genes, 14 genes were identified as shown in Figure 4. Fold changes and q-values of identified 14 genes are given in Additional file 4: Table S4. These 14 genes were correlated with body weight in both ND and HFD groups. Accordingly, these genes were associated with not only with age but also diet-induced obesity. In particular, among these 14 age and HFD responsive genes was EGF-like module containing, mucin-like, hormone receptor-like sequence 1 (Emr1) and chemokine (C-C motif) ligand 7 (Ccl7), which are both genes associated with inflammation, as well as body weight gain.
Additional file 4. Table S4.List of high-fat diet responding gene transcripts in epididymal WAT that simultaneously associated with advancing age in ND and HFD groups for 24 weeks.
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Figure 4. The list of high-fat diet responding gene transcripts in epididymal WAT that simultaneously associated with advancing age in ND and HFD groups for 24 weeks. The gene list affected by advancing age was based on continuously up- or down-regulated genes in both ND and HFD group. HFD-responsive genes were based on HFD vs ND, fold change > 2 and p-value < 0.05. ND: normal diet (AIN-76), HFD: high-fat diet (20% fat, 1% cholesterol), Cor.: Correlation Coefficient.
Time-course of transcriptional changes in adipokine, pro-inflammatory cytokine, chemokine and upstream signalling genes in visceral WAT depots during diet-induced obesity
The time-course of pro- and anti-inflammatory adipokine gene expression changes in WAT is shown in Figure 5. Consistent with plasma leptin and adiponectin levels, leptin mRNA expression was also up-regulated, while adiponectin mRNA expression was down-regulated consistently during the development of diet-induced obesity over 24 weeks. Microarray validation using via RT-qPCR revealed agreement in the time-course and pattern of changes in gene expression. There was no significant change in resistin mRNA expression.
Figure 5. RT-qPCR validation. Time-dependent fold changes in (A) Lep mRNA, (B) Adipoq mRNA and (C) Retn mRNA expression based on HFD vs.ND group over 24 weeks. Microarray and RT-qPCR data shown as means ± S.D. *p < 0.05 based on wilcoxon t-test and student's t-test, respectively. No statistical analysis, since we evaluated 1 pooled sample for microarray analysis in MAT. ND: normal diet (AIN-76), HFD: high-fat diet (20% fat, 1% cholesterol), EAT: epididymal adipose tissue, MAT: mesenteric adipose tissue, Lep: leptin, Adipoq: adiponectin, Retn: resistin.
During the development of diet-induced obesity, transcription of several pro-inflammatory cytokines and chemokines such as disintegrin and metallopeptidase domain 8 (Adam8), Emr1, interleukin 1 receptor antagonist (Il1rn), tumor necrosis factor (Tnf), serum amyloid A 3 (Saa3), integrin alpha-M (Itgam), chemokine (C-C motif) ligand 2 (Ccl2), ligand 3 (Ccl3), ligand 4 (Ccl4), ligand 6 (Ccl6), ligand 7 (Ccl7) and ligand 9 (Ccl9), were significantly elevated in epididymal WAT between week 20 and 24 (Fig. 6A). Moreover, gene expression of toll-like receptors (TLRs), interferon regulatory factor 5 (Irf5) and CD antigen families were also significantly altered by HFD in epididymal WAT. Among them Tlr2, Tlr6, Tlr7, Tlr8, Tlr13 and Trl1, Irf5 were significantly up-regulated by HFD from week 8 and week 20, respectively (Figure 6B, C). Expression of Cd9, Cd14, Cd37, Cd44, Cd68, Cd72, Cd83, Cd84, Cd180, Cd276, Cd300a and Cd300lb was also significantly elevated from week 8 to 24 in a time dependent manner (Figure 6D).
Figure 6. Effect of high-fat feeding on transcription of (A) pro-inflammatory cytokine and chemokine genes, (B) Toll-like receptors, (C) IRF5 and (D) CD families expressed in epididymal adipose tissue of C57BL/6 J mice over 24 weeks (HFD vs. ND group). mRNA expression in epididymal adipose tissue measured by the microarray analysis. Fold changes in mRNA expression (HFD vs. ND) were displayed at each time point over 24 weeks. Data shown as means ± S.D. *p < 0.05 based on wilcoxon t-test. ND: normal diet. HFD: high-fat diet.
Time-course of transcriptional changes in extracellular matrix genes, adipose tissue-expressed collagen genes and cathepsin family genes during diet-induced obesity
To identify the time-dependent effect of HFD on fibrosis relative to the ND group, we examined the levels of many key fibrotic genes (Figure 7). Lumican (Lum) and transforming growth factor β (Tgfb1) mRNA levels were up-regulated, while decorin (Dcn) mRNA levels were down-regulated by HFD in a time dependent manner. Several matrix metalloproteases (Mmp) showed time-dependent transcriptional alterations in response to HFD. Mmp2, Mmp3 and Mmp13 mRNA levels were up-regulated by HFD from week 8 to 24, whereas Mmp12 mRNA levels were significantly up-regulated earlier after week 2 in the HFD group (Figure 7A). Collagen-related mRNA levels including Col1a2, Col3a1, Col4a5, Col8a1, Col9a3 and Col16a1 were significantly higher at week 2 in the HFD group, relative to the ND group, and sharply decrease after 4 weeks (Figure 7B). Cathepsin (Cts) mRNA levels were also altered by HFD (Figure 7C), Ctsa, Ctsb, Ctsk, Ctsl, Ctss and Ctsz mRNA levels were mostly up-regulated by high-fat feeding in the epididymal WAT depot. In particular, Ctsk mRNA levels were significantly increased from week 8 in the HFD group. Ctss and Ctsz mRNA levels were significantly higher at week 2, 8, 20 and 24, while Ctsb mRNA levels were only higher at week 2 and week 24 in the HFD group.
Figure 7. Effect of high-fat feeding on transcription of key fibrotic genes in epididymal adipose tissue of C57BL/6 J mice over 24 weeks (HFD vs. ND group). (A) Extracellular matrix genes (TGF-β1, decorin, lumican and several MMPs), (B) adipose tissue-expressed collagen genes and (C) cathepsin genes in the adipose tissue measured by time-course microarrays. Fold changes in mRNA expression (HFD vs. ND) were displayed at each time-point over 24 weeks. Data shown as means ± S.D. *p < 0.05 based on wilcoxon t-test. ND: normal diet. HFD: high-fat diet.
Adipose tissue can rapidly expand in response to excess energy intake through both adipocyte hypertrophy (cell size increase) and hyperplasia (cell number increase). Excessive adipose tissue expansion in obesity is associated with adipokine dysregulation, inflammation, ECM remodeling and fibrosis particulary in visceral adipose depots. However, the time-course of these pathophysiological events and the underlying transcriptional changes in adipose tissue are not fully understood. We show adipose tissue expansion occurs in multiple visceral WAT depots early during the development of diet-induced obesity. Pro-inflammatory adipokine levels also increase early after 2–4 weeks, while anti-inflammatory adipokine levels are reduced after 20 weeks in HFD fed mice. Time-course microarray profiling revealed early and prolonged up-regulation of inflammation and immune system associated genes in the epididymal WAT depot and the smaller mesenteric WAT depot. In the later stages of diet-induced obesity, fibrosis was evident in the epididymal WAT depot. Hence the long-term diet-induced obesity model used in the present study provides a unique insight into the timing of events in visceral adipose tissue during the development of obesity.
Adipocytokine dysregulation is reported to be closely associated with obesity and plasma proinflammatory adipokines are widely reported to be elevated in obese animals. Adipokines are secreted from visceral adipose depots, hence expansion of visceral adipose tissue depots is correlated with plasma adipokine levels, but it is less well established whether adipokine are transcriptionally regulated in obesity. In the present study, plasma leptin and resistin levels were increased consistently from 4 to 24 weeks. Time-course transcriptional profiling revealed leptin mRNA levels were increased in both the epididymal and mesenteric WAT depots over 24 weeks, but changes in resistin mRNA levels were less clear. Notably, leptin mRNA levels were higher in the mesenteric WAT depot than in the epididymal WAT depot. From a structural perspective, leptin is a member of the cytokine family, and leptin receptors belong to the class-I cytokine receptor family [22,23]. Leptin can control the production and activation of pro-inflammatory cytokines such as IL-6 and TNF-α by macrophages [24,25], and is a key regulatory factor expressed in both zebrafish and mammalian obesity in lipid metabolism [26]. Resistin is also known as an adipose tissue-specific secretory factor, participating in the pathogenesis of insulin resistance, adipogenesis and inflammation in mice [27,28]. However, the time-course of plasma resistin level changes, was largely dissociated from resistin mRNA levels in the epididymal and mesenteric WAT depots. Jackson et al. [29] reported similar observations, largely that resistin mRNA levels were very low or undetectable in adipose tissue, which suggests that visceral adipocytes are not a major cell type producing resistin. Plasma resistin levels may by due to resistin production by circulating monocytes and macrophages. Like many other pro-inflammatory cytokines, resistin stimulates intracellular signalling through NF-κB activation, which in turn promotes the synthesis of other pro-inflammatory cytokines, including MCP-1, vascular cell adhesion molecule-1 (VCAM-1), as well as intercellular adhesion molecule-1 (ICAM-1), which are involved in chemotactic pathways directing leukocyte recruitment to sites of infection [30,31]. Therefore, while resistin appears not to be produced by visceral adipose tissue depots, plasma resistin may still be a player in early visceral adipose tissue inflammation via activation of pro-inflammatory signalling and leukocyte recruitment.
Circulating plasma adiponectin and adiponectin mRNA levels are reportedly decreased by HFD and inversely correlated with fat mass, and directly correlated with insulin sensitivity [32,33]. In the present study, a markedly different time-course in plasma adiponectin levels was evident with late decreases in plasma adiponectin observed, along with concomitant down-regulation of adiponectin mRNA levels in both the epididymal and mesenteric WAT depots. There have been reports indicating adiponectin is probably not a useful early biomarker of obesity. Sumiyoshi and colleagues reported that high fat feeding (45% fat, wt/wt) for 55 weeks did not alter circulating adiponectin level in C57BL/6 J mice compared with a low fat diet (3% fat, wt/wt) [34]. In accordance with our results, Park and colleague's reported that circulating adiponectin level was significantly reduced after 20 weeks of high-fat feeding (55 kcal% from fat) compared with a normal diet [35]. The lack of any early changes in plasma adiponectin and visceral adipose tissue adiponectin mRNA levels in HFD fed mice may be part of an adaptive response to protect against early inflammatory changes. There were prominent changes in adiponectin levels in both HFD and ND fed mice around 6 weeks, which we speculate may be related to sexual maturation or ageing.
Adipsin, a serine protease is synthesized and secreted by adipose cells and is found in the bloodstream [36]. In the current study, plasma adipsin levels were significantly higher in the HFD group compared to ND group from the week 2 to 24. However, it is not clear whether the higher concentration of adipsin in blood reflects increased adiposity in the HFD fed mice, because fat mass was increased over time but plasma adipsin decreased after 6 weeks regardless of diet. Previous studies have reported that blood adipsin levels are substantially increased in obese humans [37,38], but decreased in murine models of obesity [39]. Taken together, the present in-vivo observations of the time-course of various plasma adipokine levels and visceral WAT depot adipokine mRNA levels suggests leptin gene expression is up-regulated early, while adiponectin gene expression is down-regulated later in the epididymal and mesenteric WAT depots contributing to time-dependent changes in plasma adipokine levels.
We conducted in-depth time-course microarray profiling. The early and prolonged changes in the global transcriptome of both epididymal and mesenteric WAT revealed up-regulation of genes predominantly associated with immune and inflammatory system function enriched across all time-points in HFD fed mice. On the other hand, down-regulated genes were predominantly associated with monosaccharide, hexose and glucose metabolism across all time-points. Interestingly, down-regulated genes were also associated with lipid and cholesterol metabolism across all time-points although predominantly in the mesenteric WAT depot, rather than the epididymal WAT depot. In agreement with other diet-induced obesity models, functional ontology terms including sterol metabolism and acetyl-CoA biosynthesis were reportedly highly enriched among regulated genes in the mesenteric WAT depot but not in the epididymal WAT depot [40], and transcripts involved in lipid biosynthesis were up-regulated only by low fat meals [33]. Genes associated with the inflammatory response that were significantly up-regulated in the epididymal WAT depot during diet-induced obesity included pro-inflammatory cytokine and chemokine genes (TnfIl1rnSaa3Emr1Adam8ItgamCcl2Ccl3, Ccl4, Ccl6, Ccl7 and Ccl9) and their upstream signalling pathway genes such as TLRs, Irf5 and Cd14. In accordance with our study, many inflammatory genes including Ccl3, Ccl2, Saa3, Tlr13, which were highly expressed in adipose tissue of fat mouse, have been linked with obesity and/or insulin resistance [41], furthermore Emr1 and Ccl7 mRNA expression are associated with body weight gain as well as obesity-related inflammation. Adipose tissue consists of multiple cell types including adipocytes, fibroblasts, macrophages and endothelial cells. Therefore, the genes identified in the present study as differentially expressed during the development of diet-induced induced obesity will reflect overall changes in visceral adipose tissue depots rather than specific cell-types.
Recent studies have suggested some interplay between TLRs and adipokines. Lin et al. [42] suggested adipocyte Tlr2 synthesis increases upon stimulation with Tnf. Also, the expression of Tlr1-9 and Tlr11-13 in murine adipose tissue appears to be strongly regulated by leptin [43]. In the present study, the expression of Tlr1, Tlr2, Tlr6, Tlr7, Tlr8 and Tlr13 were significantly up-regulated by HFD in the epididymal WAT depot, along with Tnf and Lep expression, while expression of Adipoq was down-regulated. HFD also significantly up-regulated Irf5 in the later stages of diet-induced obesity. Irf5 is generally involved downstream of the TLR–MyD88 signalling pathway for induction of pro-inflammatory cytokines, and Irf5 is a potential target of therapeutic interventions to control harmful immune responses [44].
Of the thirteen TLRs, TLR4 was characterized first, working in conjunction with the LPS receptor CD14, TLR4 is the primary signalling receptor for gram negative bacterial lipopolysaccharide (LPS) [45]. CD14 is crucial for LPS recognition by TLR4 and cooperates with other TLRs, including TLR2 and TLR3 [46,47]. Cd180 also belongs to the family of pathogen receptors. Cd180 takes part in B-cell recognition and LPS signalling [48]. In this study, we show diet-induced obesity leads to significant induction of Cd14Cd180Cd68 and other Cd antigen genes active in the immune and inflammation system of animals. Therefore, expression of Cd antigen genes may be used as markers of visceral adipose tissue inflammation during the development of diet-induced obesity. Taken together these findings suggest that, adipose tissue expansion, and concomitant activation of TLR-mediated inflammatory signalling cascades and induction of CD antigens, causes increased expression of pro-inflammatory cytokines and chemokines, which results in chronic low-grade inflammation.
Obesity is in most, but not all humans, associated with marked changes in the secretory function of adipocytes and macrophages, together with chronic low-grade inflammation and an increased risk of developing fibrosis. A complex network of inflammatory cytokines, adipokines, transcription factors, and receptor molecules is involved in the development of adipose tissue fibrosis. In adipose tissue, fibrosis appears to be initiated in response to adipocyte hypertrophy. Adipose tissue ECM remodelling, which plays a pivotal role in adipogenesis and tissue architecture [49], is crucial to accommodate obesity-induced cellular alterations [50]. However, the persistence of an inflammatory stimulus in adipose tissue may be responsible for the excessive synthesis of ECM components and subsequent interstitial deposition of fibrotic material. Fibrosis, attributed to excessive deposition of ECM proteins, is a ubiquitous tissue response to chronic inflammation [51]. In this study, ECM gene expression was altered by HFD in a time-dependent manner. Furthermore, there was evidence of accumulation of fibrillar collagens, interspersed in between adipocytes in the visceral WAT of HFD-fed mice. Lumican (Lum) has a stimulatory effect on the epithelial-mesenchymal transition state of fibrosis, while decorin (Dcn) has an inhibitory role in transforming growth factor β (TGF-β)-induced fibrosis [52,53]. Lum mRNA levels were up-regulated, while Dcn mRNA levels were down-regulated at an early stage during the development of diet-induced obesity. Tgfb1 mRNA levels were also up-regulated in the visceral WAT of HFD-fed mice. The up-regulation of Lum and Tgfb1 mRNA levels and the down-regulation of Dcn mRNA levels were consistent with the observed development of fibrosis in visceral WAT of HFD-fed mice. Many metalloproteases (MMPs) were also altered at the mRNA level by HFD. Mmp2, 3, Mmp12 and Mmp13 are reportedly positively correlated with the degree of obesity and were up-regulated in the visceral WAT of HFD fed mice [54]. Interestingly, our detailed time-course microarray analysis over 24 weeks of HFD feeding showed that collagen mRNA levels were up-regulated shortly after the initiation of HFD feeding and then down-regulated by an unknown mechanism after 2 weeks. We suggest that up-regulation of collagen mRNA levels by HFD during the early stages of diet-induced obesity may trigger the accumulation of ECM components that ultimately leads to fibrosis which was evident in the later stages of diet-induced obesity.
The proteolytic and destructive properties of the lysosomal cathepsins play a role in degenerative, as well as chronic inflammatory diseases. Furthermore, proteases of the cathepsin family are involved in the remodelling of extracellular matrix (ECM) proteins [55]. This study indicates that members of the cathepsin family, including CtsbCtskCtslCtss and Ctsz as well as Ctsa may contribute to the pro-inflammatory and extracellular matrix remodelling in visceral WAT depots during the development of diet-induced obesity. Destruction of elastin-rich tissues during the inflammatory response is associated with local accumulation of macrophages that contain high levels of elastinolytic enzymes, such as Ctsb and Ctsl [56]. Ctss, known to degrade several components of the ECM, is also now well established as a novel biomarker of adiposity [57]. The function of cathepsin A in obesity is relatively unknown, however increases in expression of cathepsin B, D, K, S, and Z have previously been observed in obesity [58].
It is possible that some of differences in this study compared to others could be due to the lower fat content and different diet composition. Especially, while other studies used 60 kcal% fat diet consisting of soybean oil and lard, we used 39.2 kcal% from fat diet consisting of corn oil and lard. One example, several previous studies have found that hypoxia has been observed in obese adipose tissue and HIF1α (hypoxia-inducible factor 1α), a master signal mediator of hypoxia response, is significantly elevated in obese adipose tissue [4,59,60]. We also found that HIF1α gene expression tended to be higher (fold change 1.36 at HFD vs ND) at 24 week of high-fat feeding (about 39.2 kcal% from fat), but there was no statistically significant difference between the groups. However, in another experiment of ours that used commercial high fat diet with higher fat content and different fat composition (Research diets, Product No. D12451, 45 kcal% fat, 2.9% soybean oil and 20.7% lard), high fat feeding for 16 weeks significantly up-regulated HIF1α expression in adipose tissue of C57BL/6 J mice (Y. J. Kim, M. S. Choi, U. J. Jung, unpublished paper).
The present findings indicate excessive fat accumulation occurs in visceral WAT depots (epidydimal, perirenal, retroperitoneum, mesentery) early in response to HFD feeding. Pro- and anti-inflammatory adipokines including leptin and adiponectin are differentially expressed in visceral WAT and are closely associated with plasma adipokine levels during the development of diet-induced obesity. However, much wider changes occur in the immune transcriptome of visceral WAT depots, which are early and sustained. Up-regulated inflammatory genes include pro-inflammatory cytokines, chemokines and their upstream signalling pathway genes. Early changes also occur in fibrosis-related genes, extracellular matrix (ECM), collagen and cathepsin genes, but fibrosis appears in the later stages of diet-induced obesity. New therapeutic approaches targeting visceral adipose tissue genes associated with inflammation and fibrosis which are altered early during adipose tissue accumulation may help ameliorate the deleterious effects of diet-induced obesity.
DEGs: Differentially expressed genes; ND: Normal diet; HFD: High-fat diet; WAT: White adipose tissue; ECM: Extracellular matrix.
Competing interests
The author(s) declare that they have no competing interests.
Authors' contributions
EYK performed experiments and wrote the manuscript. SKS and YYC carried out the animal experiments. UJJ, EK and RAM participated in writing the manuscript. TP, JHYP, JWY and YBP analyzed the data. EYK and MSC designed the study. All authors read and approved the final manuscript.
This research was supported by the SRC program (Center for Food & Nutritional Genomics: grant number 2012–0000644) of the National Research Foundation (NRF) of Korea funded by the Ministry of Education, Science and Technology.
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The South Oldham Rotary Club honored the Students of the Month Sept. 12. The honoree from South Oldham High School is Derrek James Nichter. Nichter plans to be a teacher or work in the sports field after college. He is looking for colleges that will give him an opportunity for a baseball scholarship. At SOHS Nichter is on the baseball team and is involved in the peer tutoring program with CBE. Nichter enjoys sports, including baseball, hunting, fishing, basketball, football and swimming.
South Oldham High School teacher James Riffe, along with 19 other teachers across the state, has been accepted into the University of Louisville's Inaugural McConnell Center Teacher Scholars Program, entitled: Civil War Leadership. The program will be a year-long scholarly exploration of Civil War causes, events, implications and personalities.
Camden Station Elementary hosted a literacy night Nov. 11, an evening designed to inform parents about how to help their children be better readers. The importance of reading and writing together was stressed as parents visited stations such as John Bensing's room, where he read poetry and discussed the use of writing in art class.
Lauren Wolfe, daughter of Lisa and Jim Wolfe of Westport, made North Oldham High School history at the 57th annual National Catholic Forensic League Tournament in Appleton, Wisc. in May. Wolfe was the first NOHS speech team member to advance to the quarter-final round of competition, making her the most successful competitor in the team's history.
The Kentuckiana Chapter of Executive Women International recently announced that local resident Debra A. Carmony was awarded a $1,000 scholarship funded by the chapter's Adult Students in Scholastic Transition Program.
Stephenson participates in EKU percussion ensemble
Will Stephenson of Goshen is a member of Eastern Kentucky University's Percussion Ensemble – Steel Band, under the direction of Jason Koontz.
The 21st century. Our family was relieved to be back to the familiar world we know and love. Even though I was pleased to return, I was also thankful I'd had the opportunity to take a trip through time and learn some very valuable lessons. Because of one single penny, I had learned lessons that would stay with me the rest of my life.
Liberty Elementary teachers Lindsey Sinclair and Jennifer Heck developed the Club Liberty concept as a way to fulfill their KTIP service project. What began as a small project has led to a relaxing way for the fourth- and fifth-grade students to end the week. Through Club Liberty, fourth- and fifth-grade students have the opportunity to spend the last hour of every Friday participating in a number of different clubs and activities.
We ended up in 1997 – not the 21st century, but close. At least everything felt familiar. For one, our computer was back. Not the computer I was accustomed to, but a late '90s model. I had to dial a phone number so I could connect to the Internet. Our TV included more channels and a remote control. Also, just by turning it on, we knew all the news all around the world in just a matter of minutes.
South Oldham High hosts college night programs
Selecting a college is one of the most important and often most difficult decisions a high school student will make during his or senior year. The first step to selecting the right school is to learn what options are available. However, even if a student knows he or she wants to attend college in Kentucky, there are still more than 30 schools to research.
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