White Adipose Tissue Hypertrophy Research Articles

Oral β-RA induces metabolic rewiring leading to the rescue of diet-induced obesity

Obesity represents a significant health challenge, intricately linked to conditions such as type II diabetes, metabolic syndrome, and hepatic steatosis. Several existing obesity treatments exhibit limited efficacy, undesirable side effects or a limited capability to maintain therapeutics effects in the long-term. Recently, modulation Coenzyme Q (CoQ) metabolism has emerged as a promising target for treatment of metabolic syndrome. This potential intervention could involve the modulation of endogenous CoQ biosynthesis by the use of analogs of the precursor of its biosynthesis, such as β-resorcylic acid (β-RA). Here, we show that oral supplementation with β-RA, incorporated into the diet of diet-induced obese (DIO) mice, leads to substantial weight loss. The anti-obesity effects of β-RA are partially elucidated through the normalization of mitochondrial CoQ metabolism in white adipose tissue (WAT). Additionally, we identify an HFN4α/LXR-dependent transcriptomic activation of the hepatic lipid metabolism that contributes to the anti-obesity effects of β-RA. Consequently, β-RA mitigates WAT hypertrophy, prevents hepatic steatosis, counteracts metabolic abnormalities in WAT and liver, and enhances glucose homeostasis by reducing the insulin/glucagon ratio and plasma levels of gastric inhibitory peptide (GIP). Moreover, pharmacokinetic evaluation of β-RA supports its translational potential. Thus, β-RA emerges as an efficient, safe, and translatable therapeutic option for the treatment and/or prevention of obesity, metabolic dysfunction-associated steatotic liver disease (MASLD).

The role of the gastrointestinal barrier in obesity-associated systemic inflammation.

Systemic inflammation is a key contributor to the onset and progression of several obesity-associated diseases and is thought to predominantly arise from the hyperplasia and hypertrophy of white adipose tissue. However, a growing body of works suggests that early changes in the gastrointestinal (GI) barrier may contribute to both local, within the GI lining, and systemic inflammation in obesity. Intestinal barrier dysfunction is well-characterized in inflammatory GI disorders such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) and is known to contribute to systemic inflammation. Thus, drawing parallels between GI disorders, where intestinal permeability and systemic inflammation are prominent features, and obesity-induced GI manifestations may provide insights into the potential role of the intestinal barrier in systemic inflammation in obesity. This review summarizes the current literature surrounding intestinal barrier dysfunction in obesity and explores the potential role of intestinal hyperpermeability and intestinal barrier dysfunction in the development of systemic inflammation and GI dysfunction in obesity.

HDAC11 deficiency resists obesity by converting adipose-derived stem cells into brown adipocyte-like cells

Obesity, with complications such as type 2 diabetes, dyslipidemia, and even cancer, is rampant worldwide. Histone deacetylases (HDACs) have been extensively studied as key players in the epigenetic regulation of cellular metabolism. However, the function of HDAC11 has long been focused on the immune and nervous systems and cancer development, and its potential role in obesity has been poorly studied. We found that the expression of HDAC11 was highly upregulated in the white adipose tissue (WAT) of obese mice and was closely related to the progression of obesity. Knockdown of HDAC11 by lentiviral injection in high-fat diet-fed mice attenuated the development of obesity. Furthermore, knockdown of HDAC11 ameliorated WAT hypertrophy and induced WAT browning. At the cellular level, silencing of HDAC11 promoted the differentiation of adipose-derived stem cells (ADSCs) into brown adipocyte-like cells and inhibited the proliferation of ADSCs. More interestingly, HDAC11 expression was elevated in ADSCs isolated from obese mice, and silencing of HDAC11 facilitated the spontaneous differentiation of ADSCs into mesoderm, which is the source of adipocytes. This also superficially and effectively demonstrates the exciting prospect of HDAC11 silencing in obesity research and treatment, as a valve for “energy saving and flow reduction”.

Translational characterization of the temporal dynamics of metabolic dysfunctions in liver, adipose tissue and the gut during diet-induced NASH development in Ldlr−/−.Leiden mice

BackgroundNAFLD progression, from steatosis to inflammation and fibrosis, results from an interplay of intra- and extrahepatic mechanisms. Disease drivers likely include signals from white adipose tissue (WAT) and gut. However, the temporal dynamics of disease development remain poorly understood. MethodsHigh-fat-diet (HFD)-fed Ldlr−/−.Leiden mice were compared to chow-fed controls. At t = 0, 8, 16, 28 and 38w mice were euthanized, and liver, WAT depots and gut were analyzed biochemically, histologically and by lipidomics and transcriptomics together with circulating factors to investigate the sequence of pathogenic events and organ cross-talk during NAFLD development. ResultsHFD-induced obesity was associated with an increase in visceral fat, plasma lipids and hyperinsulinemia at t = 8w, along with increased liver steatosis and circulating liver damage biomarkers. In parallel, upstream regulator analysis predicted that lipid catabolism regulators were deactivated and lipid synthesis regulators were activated. Subsequently, hepatocyte hypertrophy, oxidative stress and hepatic inflammation developed. Hepatic collagen accumulated from t = 16 w and became pronounced at t = 28–38 w. Epididymal WAT was maximally hypertrophic from t = 8 w, which coincided with inflammation development. Mesenteric and subcutaneous WAT hypertrophy developed slower and did not appear to reach a maximum, with minimal inflammation. In gut, HFD significantly increased permeability, induced a shift in microbiota composition from t = 8 w and changed circulating gut-derived metabolites. ConclusionHFD-fed Ldlr−/−.Leiden mice develop obesity, dyslipidemia and insulin resistance, essentially as observed in obese NAFLD patients, underlining their translational value. We demonstrate that marked epididymal-WAT inflammation, and gut permeability and dysbiosis precede the development of NAFLD stressing the importance of a multiple-organ approach in the prevention and treatment of NAFLD.

Different ratios of DHA/EPA reverses insulin resistance by improving adipocyte dysfunction and lipid disorders in HFD-induced IR mice.

Objective: Insulin resistance (IR) is linked to the development of diabetes, non-alcoholic fatty liver disease (NAFLD), and cardiovascular disease (CVDs). Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) from fish oils (FOs) were used to investigate their potential in high-fat diet (HFD)-induced IR mice under different ratios. Methods: A total of 84 male C57BL/6J (6 weeks old) mice were fed with HFD containing 45% kcal from fat for 16 weeks to establish the IR model. The IR mice were then fed with HFD or HFD + 4% DHA/EPA with different ratios (3 : 1, 1.5 : 1, 1 : 1, 1 : 1.5, 1 : 3, respectively) for another 12 weeks. During the experiment, the CON group (n = 12) was set to feed with a basic diet containing 10% kcal from fat. Results: HFD feeding for 16 weeks reduced insulin sensitivity and accelerated hypertrophy of white adipose tissue (WAT). Different ratios of DHA/EPA except for 1 : 1 decreased the HOMA-IR index, average area of adipocytes, and serum MDA, but increased the protein expression of PI3K. All ratios of DHA/EPA increased the protein expression of IRS-1, GLUT4, and adiponectin. Moreover, dietary DHA/EPA changed serum fatty acid (FA) composition by increasing the serum concentration of n-3 PUFAs. DHA/EPA supplements also improved serum lipid profiles (TG/TC/LDL-c/HDL-c, FFA) and reduced the hepatic steatosis area. Conclusions: The results indicate that an appropriate higher ratio of DHA (1.5 : 1) in DHA/EPA supplementation is recommended for IR prevention.

Monochromatic Light Pollution Exacerbates High-Fat Diet-Induced Adipocytic Hypertrophy in Mice

Light pollution worldwide promotes the progression of obesity, which is widely considered a consequence of circadian rhythm disruptions. However, the role of environmental light wavelength in mammalian obesity is not fully understood. Herein, mice fed a normal chow diet (NCD) or a high-fat diet (HFD) were exposed to daytime white (WL), blue (BL), green (GL), and red light (RL) for 8 weeks. Compared with WL and RL, BL significantly increased weight gain and white adipose tissue (WAT) weight, and it disrupted glucose homeostasis in mice fed with HFD but not NCD. The analysis of WAT found that BL significantly aggravated HFD-induced WAT hypertrophy, with a decrease in IL-10 and an increase in NLRP3, p-P65, p-IκB, TLR4, Cd36, Chrebp, Srebp-1c, Fasn, and Cpt1β relative to WL or RL. More interestingly, BL upregulated the expression of circadian clocks in the WAT, including Clock, Bmal1, Per1, Cry1, Cry2, Rorα, Rev-erbα, and Rev-erbβ compared with WL or RL. However, most of the changes had no statistical difference between BL and GL. Mechanistically, BL significantly increased plasma corticosterone (CORT) levels and glucocorticoid receptors in the WAT, which may account for the changes in circadian clocks. Further, in vitro study confirmed that CORT treatment did promote the expression of circadian clocks in 3T3-L1 cells, accompanied by an increase in Chrebp, Cd36, Hsp90, P23, NLRP3, and p-P65. Thus, daily BL, rather than RL exposure-induced CORT elevation, may drive changes in the WAT circadian clocks, ultimately exacerbating lipid dysmetabolism and adipocytic hypertrophy in the HFD-fed mice.

A Botanical Mixture Consisting of Inula japonica and Potentilla chinensis Relieves Obesity via the AMPK Signaling Pathway in 3T3-L1 Adipocytes and HFD-Fed Obese Mice.

Excessive lipid accumulation in white adipose tissue (WAT) is the major cause of obesity. Herein, we investigated the anti-obesity effect and molecular mechanism of a botanical mixture of 30% EtOH extract from the leaves of Inula japonica and Potentilla chinensis (EEIP) in 3T3-L1 preadipocytes and high-fat diet (HFD)-fed obese mice. In vitro, EEIP prevented lipid accumulation by downregulating the expression of lipogenesis-related transcription factors such as CCAAT/enhancer binding protein (C/EBP)α, peroxisome proliferator-activated receptor (PPAR)γ, and sterol regulatory element binding protein (SREBP)-1 via AMP-activated protein kinase (AMPK) activation and G0/G1 cell cycle arrest by regulating the Akt-mTOR pathways without inducing cytotoxicity. In vivo, EEIP significantly reduced body weight gain and body fat mass in the group administered concurrently with HFD (pre-) or administered during the maintenance of HFD (post-) including subcutaneous, gonadal, renal, and mesenteric fats, and improved blood lipid profiles and metabolic hormones. EEIP pre-administration also alleviated WAT hypertrophy and liver lipid accumulation by reducing C/EBPα, PPARγ, and SREBP-1 expression via AMPK activation. In the brown adipose tissue, EEIP pre-administration upregulated the expression of thermogenic factors. Furthermore, EEIP improved the HFD-induced altered gut microbiota in mice. Taken together, our data indicated that EEIP improves HFD-induced obesity through adipogenesis inhibition in the WAT and liver and is a promising dietary natural material for improving obesity.

High‐Fat Diet Exacerbates Androgen‐Mediated Obesity and White Adipose Tissue Hypertrophy in a Mouse Model of Polycystic Ovary Syndrome

BackgroundPolycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in reproductive age women. PCOS is characterized by hyperandrogenemia, oligo‐ or anovulation and polycystic ovaries and is associated with obesity and white adipose tissue (WAT) dysregulation. The deleterious metabolic profile of women with PCOS is exacerbated by obesity. However, the molecular mechanisms that mediate WAT dysfunction in PCOS, as well as its modulation by the diet, are poorly understood. We aim to investigate the effect of an obesogenic diet on androgen‐mediated WAT hypertrophy by assessing the adipocyte size of the different WAT depots [mesenteric fat (MF), subcutaneous fat (SCF) and retroperitoneal fat (RPF)] using a well‐established model of PCOS in mice.MethodsThree‐week old female mice (C57BL/6J) were implanted with Silastic tubes filled with the androgen dihydrotestosterone (DHT, 8.0 mg, S.C.) or vehicle (empty tubes). Animals were fed high‐fat diet (HFD; 60% kcal fat) or low‐fat diet (LFD; 10% kcal fat, sucrose‐matched) for 90 days. Weekly body weights and body composition (EchoMRI) were assessed. Animals were sacrificed and multiple WAT depots (MF, SCF and RPF) were harvested for histological analysis. Formalin‐fixed paraffin‐embedded tissues from the three WAT depots were sectioned (5 µm thick) and stained with hematoxylin and eosin. The stained sections were imaged at 40X magnification. Adipocyte size (cross‐sectional area) was determined using ImageJ software with the Adiposoft plugin [~2,000 adipocytes/section, 3 sections/animal, n = 6/group]. GraphPad Prism 8.4.2 was used for statistical analysis, and P‐values of 0.05 were considered statistically significant.ResultsLFD‐fed DHT‐treated mice showed significant increases in body weight (28.00 ± 0.60 vs. 23.59 ± 0.41 g, p<0.05), lean mass (21.70 ± 0.30 vs. 20.04 ± 0.23 g, p<0.05), and fat mass (6.20 ± 0.50 vs. 3.42 ± 0.33 g, p<0.05) compared to their vehicle‐treated controls. Adipocyte size analysis showed that LFD‐fed DHT‐ treated mice have significantly larger adipocytes when assessed in MF (1512.0 ± 15.55 vs. 833.3 ± 6.50 µm2, p<0.05), SCF (1907.0 ± 22.04 vs. 1395.0 ± 12.43 µm2, p<0.05) and RPF (2284.0 ± 26.20 vs. 1396.0 ± 11.61 µm2, p<0.05), compared to their vehicle‐treated controls. Notably, HFD‐fed DHT‐treated mice showed greater MF and RPF adipocyte size compared to HFD‐fed vehicle‐treated mice, which was not observed in SCF. Interestingly, HFD exacerbated DHT‐mediated increases in body weight (1.54‐fold), lean mass (1.17‐fold), and fat mass (3.03‐fold) compared to LFD‐fed DHT‐treated mice. Additionally, the increase in adipocyte size in all fat depots in response to DHT was greater in mice fed HFD by 1.50‐fold compared to those fed LFD.Conclusion and significanceThe hypertrophic effect of androgens on the WAT is modulated by the diet. Increased adipocyte size is associated with insulin resistance in women with PCOS. Our results may help explain why obesity is associated with a worsened metabolic profile in women with PCOS at the cellular level. Weight loss with a low‐fat diet may be an effective approach to ameliorate WAT dysfunction and the subsequent metabolic dysregulation in PCOS.

AAV-mediated BMP7 gene therapy counteracts insulin resistance and obesity

Type 2 diabetes, insulin resistance, and obesity are strongly associated and are a major health problem worldwide. Obesity largely results from a sustained imbalance between energy intake and expenditure. Therapeutic approaches targeting metabolic rate may counteract body weight gain and insulin resistance. Bone morphogenic protein 7 (BMP7) has proven to enhance energy expenditure by inducing non-shivering thermogenesis in short-term studies in mice treated with the recombinant protein or adenoviral vectors encoding BMP7. To achieve long-term BMP7 effects, the use of adeno-associated viral (AAV) vectors would provide sustained production of the protein after a single administration. Here, we demonstrated that treatment of high-fat-diet-fed mice and ob/ob mice with liver-directed AAV-BMP7 vectors enabled a long-lasting increase in circulating levels of this factor. This rise in BMP7 concentration induced browning of white adipose tissue (WAT) and activation of brown adipose tissue, which enhanced energy expenditure, and reversed WAT hypertrophy, hepatic steatosis, and WAT and liver inflammation, ultimately resulting in normalization of body weight and insulin resistance. This study highlights the potential of AAV-BMP7-mediated gene therapy for the treatment of insulin resistance, type 2 diabetes, and obesity.

What's up with WAT: attempting to mimic adipose tissue in vitro.

What's up with WAT: attempting to mimic adipose tissue in vitro.

Dysosmobacter welbionis is a newly isolated human commensal bacterium preventing diet-induced obesity and metabolic disorders in mice

ObjectiveTo investigate the abundance and the prevalence of Dysosmobacter welbionis J115T, a novel butyrate-producing bacterium isolated from the human gut both in the general population and in subjects with metabolic...

Co-Treatment with Cefotaxime and High-Fructose Diet Inducing Nonalcoholic Fatty Liver Disease and Gut Microbial Dysbiosis in Mice

High fructose diet causes metabolic syndrome and induces host gut microbial dysbiosis and related obesity and nonalcoholic fatty liver disease (NAFLD). Several antibiotic treatments could prevent fatty liver. However, there are studies that have demonstrated that a high-fructose diet could influence the gut microbial dysbiosis and induce fatty liver. The purpose of this study was performed to partially modify the gut bacterial composition with a single cefotaxime treatment, which might affect the fructose-induced NAFLD severity. The C57BL/6JNarl male mice were divided into four groups including vehicle/chow diet (VE-CD), vehicle/high-fructose diet (VE-FD), antibiotic (cefotaxime (CF))/CD, and CF/FD. The results showed that body weight gain, moderate hepatic steatosis severity, epididymal white adipose tissue hypertrophy, and insulin resistance occurrence with NAFLD-related symptoms were observed only in the CF-FD group. The raised protein expression of hepatic lipogenesis was observed in the CF-FD group, but lipolysis protein expression was no difference. The diversity and composition of microbiota were significantly reduced in the CF-FD group. The Erysipelatoclostridium, Enterobacteriaceae, Lachnospiraceae, and Escherichia Shigella were in increased abundance in the feces of CF-FD group compared with VE-FD group. The novel model reveals that particular antibiotics such as cefotaxime co-treatment with high-fructose diet may affect the gut microbiota accelerating the NAFLD and obesity.

Adipokines in obesity and metabolic diseases

Adipose tissue secretes many adipokines that regulate important physiological functions. Growing studies have highlighted that these bioactive molecules may contribute to the development of metabolic and cardiovascular diseases. Adipokines exert systemic metabolic effects and independent activity on numerous cells of the cardiovascular system, including cardiomyocytes and vascular cell walls. Adiponectin shows anti-inflammatory and anti-atherosclerotic activity on blood vessels. Conversely, resistin is endowed with pro-inflammatory effects and stimulates the proliferation of smooth muscle cells, thus promoting the development of atherosclerotic plaque. Leptin plays an important role in cardiac remodeling and blood pressure regulation through the activation of the sympathetic system. Obesity is a pathological condition associated with hypertrophy of white adipose tissue, which stimulates the production of pro-inflammatory adipokines while, it reduces the production of anti-inflammatory adipokines. The delicate balance among the production of pro-and anti-inflammatory molecules generated by adipose tissue affects, not only the development of metabolic complications associated with obesity, but also the onset and progression of atherosclerosis. Therefore, adipokines may be regarded as potential agents of clinical interest in the treatment of a wide range of metabolic disorders and as potential biomarkers useful for early detection of metabolic, cardiovascular and inflammatory diseases.

Fasting and refeeding cycles alter subcutaneous white depot growth dynamics and the morphology of brown adipose tissue in female rats.

Intermittent food restriction (IFR) is used mainly for weight loss; however, its effects on adipose tissue are not known when alternating with an obesogenic diet. To demonstrate its effects on morphological dynamics of fat deposits, female Wistar rats were distributed into groups: standard control (ST-C), with commercial diet; DIO control (DIO-C), with a diet that induces obesity (DIO) during the first and last 15 d, replaced by a standard diet for thirty intermediate days; standard restricted (ST-R), with standard diet during the first and last 15 d, with six cycles of IFR at 50 % of ST-C; and DIO restricted (DIO-R), in DIO during the first and last 15 d, with six cycles of IFR at 50 % of DIO-C. At 105 d of life, white adipose tissue (WAT) and brown adipose tissue (BAT) deposits were collected, weighed and histology performed. The DIO-R group showed higher total food intake (DIO-R 10 768·0 (SEM 357·52) kJ/g v. DIO-C 8868·6 (SEM 249·25) kJ/g, P < 0·0001), energy efficiency during RAI (DIO-R 2·26 (SEM 0·05) g/kJ v. DIO-C 0·70 (SEM 0·03) g/kJ, P < 0·0001) and WAT (DIO-R 5·65 (SEM 0·30) g/100 g v. DIO-C 4·56 (SEM 0·30) g/100 g) than their respective control. Furthermore, IFR groups presented hypertrophy of WAT and BAT, as well as fibrosis in BAT. Thus, IFR can establish prospective resistance to weight loss by favouring changes in adipose tissue morphology, increased energy intake and efficiency. Finally, the DIO diet before and after IFR aggravates the damages caused by the restriction.

Protective Effects of Eicosapentaenoic Acid Plus Hydroxytyrosol Supplementation Against White Adipose Tissue Abnormalities in Mice Fed a High-Fat Diet.

Objective: Obesity induced by high-fat diet (HFD) elicits white adipose tissue dysfunction. In this study, we have hypothesized that the metabolic modulator eicosapentaenoic acid (EPA) combined with the antioxidant hydroxytyrosol (HT) attenuates HFD-induced white adipose tissue (WAT) alterations. Methods: C57BL/6J mice were administered with a HFD (60% fat, 20% protein, 20% carbohydrates) or control diet (CD; 10% fat, 20% protein, 70% carbohydrates), with or without EPA (50 mg/kg/day), HT (5 mg/kg/day), or both for 12 weeks. Determinations in WAT include morphological parameters, EPA and docosahexaenoic acid content in phospholipids (gas chromatography), lipogenesis, oxidative stress (OS) and inflammation markers, and gene expression and activities of transcription factors, such as sterol regulatory element-binding protein-1c (SREBP-1c), peroxisome proliferator-activated receptor-gamma (PPAR-γ), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) (p65 subunit) and nuclear factor erythroid 2-related factor 2 (Nrf2) (quantitative polymerase chain reaction and enzyme linked immunosorbent assay). Results: HFD led to WAT hypertrophy in relation to PPAR-γ downregulation. WAT metabolic dysfunction was characterized by upregulation of lipogenic SREBP-1c system, mitochondrial energy metabolism depression, loss of the antioxidant Nrf2 signaling with OS enhancement, n-3 long-chain polyunsaturated fatty acids depletion and activation of the pro-inflammatory NF-κB system. EPA and HT co-supplementation diminished HFD-dependent effects additively, reaching values close or similar to controls. Conclusion: Data presented strengthen the importance of combined protocols such as EPA plus HT to attenuate metabolic-inflammatory states triggered by obesity.

Ulmus parvifolia Jacq. Exhibits Antiobesity Properties and Potentially Induces Browning of White Adipose Tissue

The bark of Ulmus parvifolia Jacq. (UP) was traditionally used as a diuretic and to treat intestinal inflammation. With modern evidence of the correlation of diuretics, gut inflammation, and obesity, our study has shown the antiobesity effects of the bark of UP. UP treatment reduced lipid production and adipogenic genes in vitro. In vivo studies revealed that UP 100 mg/kg and UP 300 mg/kg treatment significantly reduced mouse weight without reducing food intake, indicating increased energy expenditure. UP significantly reduced the weight of epididymal and subcutaneous adipose tissue and decreased liver weight. Histological analysis revealed improvement in the progression of nonalcoholic fatty liver disease and epididymal white adipose tissue hypertrophy induced by a HFD. Real-Time PCR of epididymal adipose tissue revealed significant increases of uncoupling protein-1 (UCP-1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) expression after UP 300 mg/kg treatments. Phosphorylation of AMP-activated protein α (AMPKα) was increased, while phosphorylation of Acetyl-CoA Carboxylase (ACC) was reduced. Our findings reveal the ability of UP to reduce the occurrence of obesity through increased browning of white adipose tissue via increased AMPKα, PPARγ, PGC-1α, and UCP-1 expression.

Deletion of the Glutaredoxin-2 Gene Protects Mice from Diet-Induced Weight Gain, Which Correlates with Increased Mitochondrial Respiration and Proton Leaks in Skeletal Muscle.

Aims: The aim of this study was to determine whether deleting the gene encoding glutaredoxin-2 (GRX2) could protect mice from diet-induced weight gain. Results: Subjecting wild-type littermates to a high fat diet (HFD) induced a significant increase in overall body mass, white adipose tissue hypertrophy, lipid droplet accumulation in hepatocytes, and higher circulating insulin and triglyceride levels. In contrast, GRX2 heterozygotes (GRX2+/-) fed an HFD had a body mass, white adipose tissue weight, and hepatic and circulating lipid and insulin levels similar to littermates fed a control diet. Examination of the bioenergetics of muscle mitochondria revealed that this protective effect was associated with an increase in respiration and proton leaks. Muscle mitochondria from GRX2+/- mice had a ∼2- to 3-fold increase in state 3 (phosphorylating) respiration when pyruvate/malate or succinate served as substrates and a ∼4-fold increase when palmitoyl-carnitine was being oxidized. Proton leaks were ∼2- to 3-fold higher in GRX2+/- muscle mitochondria. Treatment of mitochondria with either guanosine diphosphate, genipin, or octanoyl-carnitine revealed that the higher rate of O2 consumption under state 4 conditions was associated with increased leaks through uncoupling protein-3 and adenine nucleotide translocase. GRX2+/- mitochondria also had better protection from oxidative distress. Innovation: For the first time, we demonstrate that deleting the Grx2 gene can protect from diet-induced weight gain and the development of obesity-related disorders. Conclusions: Deleting the Grx2 gene protects mice from diet-induced weight gain. This effect was related to an increase in muscle fuel combustion, mitochondrial respiration, proton leaks, and reactive oxygen species handling. Antioxid. Redox Signal. 31, 1272-1288.

Epigenetic regulation of diabetogenic adipose morphology

ObjectiveHypertrophic white adipose tissue (WAT) morphology is associated with insulin resistance and type 2 diabetes. The mechanisms governing hyperplastic versus hypertrophic WAT expansion are poorly understood. We assessed if epigenetic modifications in adipocytes are associated with hypertrophic adipose morphology. A subset of genes with differentially methylated CpG-sites (DMS) in the promoters was taken forward for functional evaluation. MethodsThe study included 126 women who underwent abdominal subcutaneous biopsy to determine adipose morphology. Global transcriptome profiling was performed on WAT from 113 of the women, and CpG methylome profiling on isolated adipocytes from 78 women. Small interfering RNAs (siRNA) knockdown in human mesenchymal stem cells (hMSCs) was used to assess influence of specific genes on lipid storage. ResultsA higher proportion of CpG-sites were methylated in hypertrophic compared to hyperplastic WAT. Methylation at 35,138 CpG-sites was found to correlate to adipose morphology. 2,102 of these CpG-sites were also differentially methylated in T2D; 98% showed directionally consistent change in methylation in WAT hypertrophy and T2D. We identified 2,508 DMS in 638 adipose morphology-associated genes where methylation correlated with gene expression. These genes were over-represented in gene sets relevant to WAT hypertrophy, such as insulin resistance, lipolysis, extracellular matrix organization, and innate immunity. siRNA knockdown of ADH1B, AZGP1, C14orf180, GYG2, HADH, PRKAR2B, PFKFB3, and AQP7 influenced lipid storage and metabolism. ConclusionCpG methylation could be influential in determining adipose morphology and thereby constitute a novel antidiabetic target. We identified C14orf180 as a novel regulator of adipocyte lipid storage and possibly differentiation.

Noggin depletion in adipocytes promotes obesity in mice

ObjectiveObesity has increased to pandemic levels and enhanced understanding of adipose regulation is required for new treatment strategies. Although bone morphogenetic proteins (BMPs) influence adipogenesis, the effect of BMP antagonists such as Noggin is largely unknown. The aim of the study was to define the role of Noggin, an extracellular BMP inhibitor, in adipogenesis. MethodsWe generated adipose-derived progenitor cells and a mouse model with adipocyte-specific Noggin deletion using the AdiponectinCre transgenic mouse, and determined the adipose phenotype of Noggin-deficiency. ResultsOur studies showed that Noggin is expressed in progenitor cells but declines in adipocytes, possibly allowing for lipid accumulation. Correspondingly, adipocyte-specific Noggin deletion in vivo promoted age-related obesity in both genders with no change in food intake. Although the loss of Noggin caused white adipose tissue hypertrophy, and whitening and impaired function in brown adipose tissue in both genders, there were clear gender differences with the females being most affected. The females had suppressed expression of brown adipose markers and thermogenic genes including peroxisome proliferator activated receptor gamma coactivator 1 alpha (PGC1alpha) and uncoupling protein 1 (UCP1) as well as genes associated with adipogenesis and lipid metabolism. The males, on the other hand, had early changes in a few BAT markers and thermogenic genes, but the main changes were in the genes associated with adipogenesis and lipid metabolism. Further characterization revealed that both genders had reductions in VO2, VCO2, and RER, whereas females also had reduced heat production. Noggin was also reduced in diet-induced obesity in inbred mice consistent with the obesity phenotype of the Noggin-deficient mice. ConclusionsBMP signaling regulates female and male adipogenesis through different metabolic pathways. Modulation of adipose tissue metabolism by select BMP antagonists may be a strategy for long-term regulation of age-related weight gain and obesity.

Transforming Growth Factor-β3 Regulates Adipocyte Number in Subcutaneous White Adipose Tissue

White adipose tissue (WAT) mass is determined by adipocyte size and number. While adipocytes are continuously turned over, the mechanisms controlling fat cell number in WAT upon weight changes are unclear. Herein, prospective studies of human subcutaneous WAT demonstrate that weight gain increases both adipocyte size and number, but the latter remains unaltered after weight loss. Transcriptome analyses associate changes in adipocyte number with the expression of 79 genes. This gene set is enriched for growth factors, out of which one, transforming growth factor-β3 (TGFβ3), stimulates adipocyte progenitor proliferation, resulting in a higher number of cells undergoing differentiation invitro. The relevance of these observations was corroborated invivo where Tgfb3+/- mice, in comparison with wild-type littermates, display lower subcutaneous adipocyte progenitor proliferation, WAT hypertrophy, and glucose intolerance. TGFβ3 is therefore a regulator of subcutaneous adipocyte number and may link WAT morphology to glucose metabolism.