Capacity Of White Adipose Tissue Research Articles

Prenatal PPARα Activation Moved Forward Transient Browning of WAT at Neonates and Increased HFD-Induced UCP1 Expression in WAT of Male Mice at Adulthood

Abstract Objectives To test the hypothesis that prenatal administration of PPARα agonist clofibrate may increase the developmental beige adipocytes and permanently increased the browning capacity of white adipose tissue (WAT). Methods Pregnant C57BL/6 J mice received a basal diet, without (C) or with 0.5% clofibrate (CF, a PPARα agonist) throughout pregnancy. After parturition, only male offspring were used; all suckled their mothers (who were eating the C diet) and after weaning, they ate a standard chow diet for 4 wk, followed by a high-fat diet (HFD) for 5 wk. Results CF administration significantly increased the expression of PPARα and its target genes. CF elevated serum concentrations and hepatic expression of FGF21 (a thermogenic hormone) in fetuses, with a return to basal levels after CF withdrawal. At postnatal day 84 (P84), CF-offspring had significantly higher mRNA and protein levels of UCP1 in response to HFD in inguinal (iWAT) but not in visceral fats. Based on UCP1 levels in iWAT on P7, P14, and P21, the appearance of the transient brown-adipocyte phenotype seemed to be hastened by prenatal CF exposure. The mRNA level of UCP1 is peaked at P14 in CF-offspring, unlike C-offspring which peaked at P21. However, the mRNA level of beige cell markers (Cd137, Tmem26, Tbx1) maintained the same across this time window (P7–21). Microarray analysis of global gene expression in iWAT during this time window is conducting, as well as serum level of leptin, since leptin surge is essential to the formation of beige adipocytes during this time window. Conclusions Giving CF to pregnant mice programmed greater HFD-induced WAT browning in subcutaneous, but not in visceral fat, in their male offspring at adulthood. We foresee the transient browning of iWAT occurred at critical window may offer clues for elucidating this interesting phenomenon. Funding Sources Ministry of Science and Technology, Taiwan.

Neonatal Resveratrol and Nicotinamide Riboside Supplementations Sex-Dependently Affect Beige Transcriptional Programming of Preadipocytes in Mouse Adipose Tissue.

Nutritional programming of the thermogenic and fuel oxidation capacity of white adipose tissue (WAT) through dietary interventions in early life is a potential strategy to enhance future metabolic health. We previously showed that mild neonatal supplementations with the polyphenol resveratrol (RSV) and the vitamin B3 form nicotinamide riboside (NR) have sex-dependent, long-term effects on the thermogenic/oxidative phenotype of WAT of mice in adulthood, enhancing this phenotype selectively in male animals. Here, we tested the hypothesis that these dietary interventions may impact the commitment of progenitor cells resident in the developing WAT toward brown-like (beige) adipogenesis. NMRI mice received orally from postnatal day 2–20 (P2–20) a mild dose of RSV or NR, in independent experiments; control littermates received the vehicle. Sex-separated primary cultures were established at P35 from the stromovascular fraction of inguinal WAT (iWAT) and of brown adipose tissue (BAT). Expression of genes related to thermogenesis and oxidative metabolism was assessed in the differentiated cultures, and in vivo in the iWAT depot of young (P35) animals. Neonatal RSV and NR treatments had little impact on the animals’ growth during early postnatal life and the expression of thermogenesis- and oxidative metabolism-related genes in the iWAT depot of young mice. However, the expression of brown/beige adipocyte marker genes was upregulated in the iWAT primary cultures from RSV supplemented and NR supplemented male mice, and downregulated in those from supplemented female mice, as compared to cultures derived from sex-matched control littermates. RSV supplementation had similar sex-dependent effects on the expression of thermogenesis-related genes in the BAT primary cultures. A link between the sex-dependent short-term effects of neonatal RSV and NR supplementations on primary iWAT preadipocyte differentiation observed herein and their previously reported sex-dependent long-term effects on the thermogenic/oxidative capacity of adult iWAT is suggested. The results provide proof-of-concept that the fate of preadipocytes resident in WAT of young animals toward the beige adipogenesis transcriptional program can be modulated by specific food bioactives/micronutrients received in early postnatal life.

Involvement of acetyl-CoA-producing enzymes in the deterioration of the functional potential of adipose-derived multipotent cells from subjects with metabolic syndrome

ObjectiveThe expansion capacity of white adipose tissue influences the distribution of fat depots in the body, the visceral accumulation of which is linked to metabolic syndrome, regardless of the degree of obesity of the subjects. Alterations in the adipose tissue-derived mesenchymal stem cells (ASCs) may contribute to the adipose tissue remodeling associated with metabolic syndrome and impact the regional distribution of adipose tissue by generating inherently dysfunctional adipocytes. Here we examine the expression levels of acetyl-CoA-producing enzymes and their relationship with the lipogenic, antioxidant and oxidative potential of adipocytes generated from visceral ASCs (adipo-visASCs) and subcutaneous ASCs (adipo-subASCs) from subjects with different metabolic profiles. Materials/MethodsPaired samples of visceral and subcutaneous adipose tissue were processed to isolate the respective ASCs from normal-weight (Nw) subjects and obese patients with metabolic syndrome (METS) and without METS (NonMETS). qPCR was used to quantify the expression levels of the genes studied in both adipo-ASCs from the patient groups and those generated after silencing by small interfering RNA of acetyl-CoA-producing enzymes. The accumulation of lipids was quantified by absorbance. ResultsNo significant differences in cell yield or CD34+CD31−CD45− ASC percentage were observed between the different patient groups. Unlike adipo-visASCs, adipo-subASCs from METS patients showed a decrease in expression levels of acetyl-CoA-producing enzymes as well as proteins linked to lipogenesis, antioxidant defense and fatty acid oxidation. Transcriptional silencing of acetyl-CoA-producing enzymes in adipo-subASCs reduced lipid accumulation and affected transcription levels of lipogenic and antioxidant defense proteins. ConclusionsAdipo-subASCs may be more susceptible than adipo-visASCs to deterioration of the lipogenic, oxidative and antioxidant potential associated with metabolic syndrome. Intrinsic alterations in transcription levels of acetyl-CoA-producing enzymes may contribute to the metabolic reprogramming of adipo-subASCs from METS patients.

MKK6 controls T3-mediated browning of white adipose tissue

Increasing the thermogenic capacity of adipose tissue to enhance organismal energy expenditure is considered a promising therapeutic strategy to combat obesity. Here, we report that expression of the p38 MAPK activator MKK6 is elevated in white adipose tissue of obese individuals. Using knockout animals and shRNA, we show that Mkk6 deletion increases energy expenditure and thermogenic capacity of white adipose tissue, protecting mice against diet-induced obesity and the development of diabetes. Deletion of Mkk6 increases T3-stimulated UCP1 expression in adipocytes, thereby increasing their thermogenic capacity. Mechanistically, we demonstrate that, in white adipose tissue, p38 is activated by an alternative pathway involving AMPK, TAK, and TAB. Our results identify MKK6 in adipocytes as a potential therapeutic target to reduce obesity.

P 110 - Glutathione deprivation improves oxidative capacity but disrupts endocrine role of white adipose tissue in overall metabolic homeostasis

Clarification of molecular mechanisms underlying lipid buffering capacity of white adipose tissue (WAT) may aid in the improvement of therapeutic options for obesity and diabetes prevention. Results of our studies have shown that cold-induced regression of WAT involves transient increase of tissue lipid oxidation, uncoupling capacity, an occurrence of browning allsynchronized with increase in adiponectin and resistin synthesis and profound glutathione (GSH) depletion. This GSH decrease prompted us to examine if a decrement of GSH a priori recapitulates cold-induced favorable phenotype of WAT. To this end, room-temperature and cold-exposed rats were treated with L-buthionine-S,R-sulfoximine (BSO). Indeed, BSO treatment reduced rat body weight and lipid content in fat tissue on account of increased OXPHOS and uncoupling capacity of WAT in both, cold-exposed and room-temperature maintained rats. However, in comparison to control, BSO decreased expressions of adiponectin and resistin at room temperature and attenuated their adaptive increase on cold exposure. Decrement of GSH raise lipid burning phenotype in WAT, but it may interfere with endocrine role of WAT in overall metabolic homeostasis maintenance.

Prior Exercise Training Alters the Response of White and Brown Adipose Tissue to Cold Stress

Brown adipose tissue is a thermogenic tissue bed that produces heat in conditions of cold environmental temperatures. While possessing much lower oxidative capacity than brown adipose tissue, recent findings have suggested that exercise training can increase the thermogenic capacity of white adipose tissue. What is not known is if exercise training can alter the response of an animal to cold stress. To address this question, male C57BL/6 mice were subject to either exercise training by voluntary wheel running (EX) or a sedentary (SED) intervention for 12 days. EX mice ran approximately 6km/day, which led to decreased body weight and increased glucose tolerance, while maintaining a similar pattern of food intake to SED. Mice were then further divided into groups that would be kept at room temperature (22°C) or a cold challenge of 4°C for 48‐hrs, thus we examined four groups in this study; (i) SED kept at room temperature (SRT), (ii) exercise trained kept at room temperature (EXRT), (iii) SED kept at 4°C (SC), and (iv) EX kept at 4°C (EXC). Rectal temperatures (Tb) of SC and EXC were lower than that of SRT and EXRT, and the initial drop in Tb of EXC was less than that observed in the SC 2‐hours following the start of the cold, however this difference was not maintained throughout the rest of the cold exposure. 48‐hrs of cold exposure led to reductions in body weight and epididymal and subcutaneous adipose tissue mass in the SED but not EX mice. Conversely, interscapular brown adipose tissue mass was increased following cold exposure in previously EX but not SED animals Taken together, our data demonstrates a unique effect of prior exercise on altering the response of adipose tissue to cold stress.Support or Funding InformationD.C.W. is a Tier II Canada Research Chair. This work was funded by an NSERC Discovery Grant to D.C.W.

Oncostatin m impairs brown adipose tissue thermogenic function and the browning of subcutaneous white adipose tissue.

Since oncostatin m (OSM) is elevated in adipose tissue in conditions of obesity and type 2 diabetes in mice and humans, the aim of this study was to determine whether this cytokine plays a crucial role in the impairment of brown adipose tissue (BAT) activity and browning capacity that has been observed in people with obesity. C57BL/6J mice rendered obese by high-fat diet, their lean controls, and C57BL/6J mice fed a standard diet and implanted subcutaneously with a mini pump through a surgical procedure to deliver OSM or placebo were used. Preadipocytes or fully differentiated brown adipocytes were treated with OSM or vehicle with or without norepinephrine before harvesting. RNA was extracted and processed for qPCR analysis. Media from mature adipocytes was also collected to measure glycerol levels. Studies demonstrated that OSM gene expression was increased in BAT of mice fed a high-fat diet. In addition, exogenous OSM impaired BAT activity and the browning capacity of white adipose tissue in vitro and in vivo. Overall, the results reveal a negative role for OSM on BAT and on the browning of white adipose tissue. Therefore, further studies are necessary to demonstrate whether OSM inhibition is a potential treatment for metabolic disorders.

Exercise-Mediated Effects on White and Brown Adipose Tissue Plasticity and Metabolism.

Exercise training increases the thermogenic capacity of white adipose tissue (WAT), an effect known as "browning" of the WAT. Here, we discuss how this affects whole-body energy homeostasis. We put forth the hypothesis that browning of the subcutaneous WAT allows the organism to adjust its metabolic rate according to energy availability while coping with increased heat production through exercise.

Fatty acid-induced mitochondrial uncoupling in adipocytes is not a promising target for treatment of insulin resistance unless adipocyte oxidative capacity is increased

The release of fatty acids from white adipose tissue is regulated at several levels. We have examined the suggestion that fatty acid release might be diminished by upregulation of mitochondrial fatty acid oxidation in the adipocyte, through increasing mitochondrial uncoupling. The intrinsic oxidative capacity of white adipose tissue is low, and older studies suggest that there is little fatty acid oxidation in white adipocytes, human or rodent. We have examined data on fatty acid metabolism and O(2) consumption in human white adipose tissue in vivo, and conclude that increasing fatty acid oxidation within the oxidative capacity of the tissue would produce only small changes (a few percent) in fatty acid release. The major locus of control of fatty acid release beyond the stimulation of lipolysis is the pathway of fatty acid esterification, already probably targeted by the thiazolidinedione insulin-sensitising agents. An alternative approach would be to upregulate the mitochondrial capacity of the adipocyte. We review proof-of-concept studies in which the phenotype of the white adipocyte has been changed to resemble that of the brown adipocyte by expression of peroxisome proliferator-activated receptor coactivator-1alpha. This increases oxidative capacity and also leads to fatty acid retention through upregulation of glycerol-3-phosphate production, and hence increased fatty acid re-esterification. We conclude that prevention or treatment of insulin resistance through alteration of adipocyte fatty acid handling will require more than a simple alteration of the activity of mitochondrial beta-oxidation within normal limits.

Onset and development of hypertriglyceridemia in the Zucker rat ( [formula omitted

Triglyceridemia was studied in genetically obese Zucker rats ( fa fa ) and their lean littermates aged 1–8 wk. Hypertriglyceridemia was manifest in the obese from 2 wk onwards. Hepatic triacylglycerol secretion rate (TGSR) measured after administration of Triton WR-1339, was similar in obese and lean pups aged 2 wk. At 4 wk TGSR was twice as high in the obese as in the lean. Lipoprotein lipase (LPL) activity was abnormal in the tissues of obese animals, being either increased in white adipose tissue from 1 wk onwards or decreased in brown adipose tissue and cardiac and skeletal muscle from 2 wk onwards. The simultaneous appearance in the 2-wk-old obese of a decrease in LPL activity of the latter tissues, and hypertriglyceridemia strongly suggests a cause-effect relationship particularly since TGRS is normal. After weaning, LPL capacity of white adipose tissue in the obese, although considerably increased, was apparently not high enough to compensate for both an increased TGSR and a decreased LPL activity in other tissues.

Seasonal changes in adipose tissue lipogenesis in the hibernator

1. 1. Seasonal effects on lipogenesis from glucose or acetate by white and brown adipose tissue preparations from the ground squirrel were studied. 2. 2. Lipogenic capacity of white adipose tissue follows a yearly cycle, reaching a maximal rate in June, declining in September, and being lowest in January. 3. 3. Compared with white adipose tissue, a low rate of fatty add synthesis was found in brown adipose tissue. Maximal rate of acetate oxidation in brown adipose tissue was observed in arousing animals.