Subcutaneous Adipose Tissue Mass Research Articles

Erratum: The role of visceral adipose tissue on improvement in insulin sensitivity following Roux-en-Y gastric bypass: a study in Chinese diabetic patients with mild and central obesity.

[This corrects the article DOI: 10.1093/gastro/goy024.].

Abdominal fat depots, insulin resistance, and incident diabetes mellitus in women with and without HIV infection.

The aim of this study was to determine the associations between visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue (SAT) mass with homeostatic model assessment-insulin resistance (HOMA-IR) and incidence of diabetes mellitus in women with and without HIV infection. Cross-sectional design for associations between abdominal fat and HOMA-IR; longitudinal design for associations between abdominal fat and incident diabetes. We assessed associations between dual X-ray absorptiometry scan-derived VAT and SAT with HOMA-IR in a subsample from the Women's Interagency HIV Study (n = 226 with and n = 100 without HIV) using linear regression. We evaluated associations of VAT, SAT and HOMA-IR with incident diabetes mellitus using Cox proportional hazards models. VAT mass was positively associated with log HOMA-IR in fully adjusted linear regression models stratified by HIV serostatus, including adjustment for SAT. During median follow-up of 10.6 years, incidence of diabetes was 1.63 [95% confidence interval (95% CI) 1.15-2.31] and 1.32 [95% CI 0.77-2.28] cases per 100 person-years in women with and without HIV (P = 0.52). In a fully adjusted model, baseline VAT (hazard ratio 2.64 per kg; 95% CI 1.14-6.12; P = 0.023) and SAT (hazard ratio 1.34 per kg; 95% CI 0.73-2.45; P = 0.35) were associated with incident diabetes, but the latter was not statistically significant. VAT mass was independently associated with HOMA-IR in women with and without HIV and was independently associated with future development of diabetes.

The role of visceral adipose tissue on improvement in insulin sensitivity following Roux-en-Y gastric bypass: a study in Chinese diabetic patients with mild and central obesity.

BackgroundMost Chinese patients with type 2 diabetes mellitus (T2DM) have mild obesity and central obesity. Central obesity is combined with insulin resistance. The aim of this study was to assess the effect of abdominal adipose tissue on insulin-sensitivity improvement after Roux-en-Y gastric bypass (RYGB) in Chinese diabetic patients with mild and central obesity.MethodsSeventeen T2DM patients with a mean body mass index of 30.3 kg/m2 were scheduled for laparoscopic RYGB. A hyperinsulinemic-euglycemic clamp and dual-energy X-ray absorptiometry were performed prior to surgery and 3 months after RYGB. The primary end points were the correlations between insulin sensitivity and abdominal adipose tissue, including visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), before and 3 months after RYGB.ResultsIndices of peripheral insulin sensitivity, including glucose-disposal rate (M value) and glucose infusion rate, were significantly increased after RYGB. Body-fat mass, VAT and SAT were significantly reduced after RYGB. The pre-operative M value was significantly correlated with VAT mass (r = –0.57, P = 0.02), but not correlated with SAT mass. M value changes after RYGB were highly correlated with changes in VAT mass (r = –0.59, P = 0.01), percentage of VAT mass (r = –0.66, P < 0.01), VAT area (r = –0.56, P = 0.02) and percentage of VAT area (r = –0.57, P = 0.02).ConclusionsA significant correlation was observed between increased peripheral insulin sensitivity and decreased VAT following RYGB in Chinese patients with mild and central obesity. VAT and SAT were significantly decreased with improved insulin sensitivity after RYGB. VAT mass may be considered as an indication for gastric bypass during patient selection.

Adipocyte-specific deficiency of Nfe2l1 disrupts plasticity of white adipose tissues and metabolic homeostasis in mice

The maintenance of healthy adipose tissues is essential for efficient regulation of energy homeostasis. Nuclear factor-erythroid 2-related factor 1 (NFE2L1, also known as Nrf1), a CNC-bZIP protein, is a master regulator of the cellular adaptive response to stresses. To investigate the role of NFE2L1 in adipocytes, we bred a line of mice with adipocyte-specific Nfe2l1 knockout (Nfe2l1(f)-KO), and found that Nfe2l1(f)-KO mice exhibited a dramatically reduced subcutaneous adipose tissue (SAT) mass, insulin resistance, adipocyte hypertrophy, and severe adipose inflammation. Mechanistic studies revealed that Nfe2l1 deficiency may disturb the expression of lipolytic genes in adipocytes, leading to adipocyte hypertrophy followed by inflammation, pyroptosis, and insulin resistance. Our findings reveal a novel role for NFE2L1 in regulating adipose tissue plasticity and energy homeostasis.

Fibroblast Growth Factor-21 Maintains Glucose Homeostasis through Influencing the Expansion and Function of Subcutaneous Adipose Tissue

Fibroblast growth factor 21 (FGF-21) has been extensively studied in recent years due to its multiple therapeutic benefits for a cluster of obesity-related cardiometabolic complications. However, an unsolved puzzle is that despite its pleiotropic metabolic benefits, FGF-21 is paradoxically elevated in obesity and diabetes in both animals and humans. Its pathophysiological relevance in response to excess energy intake remains poorly understood. Here we provide both clinical and animal evidences demonstrating that elevated endogenous FGF-21 in obesity serves as a defense mechanism against systemic insulin resistance. Serum FGF-21 levels were positively associated with subcutaneous fat area in subjects with insulin-sensitive overweight/obesity. Furthermore, FGF-21 knockout mice (FGF-21KO) showed much less subcutaneous adipose tissue (SAT) mass and were more insulin resistant when fed with high-fat diet. Replenishment of recombinant FGF-21 to a level equivalent to those occurring in diet-induced obesity restored SAT mass and reversed insulin resistance in FGF-21KO but not in adipose-specific βklotho knockout mice. Moreover, transplantation of SAT from wild type to FGF-21KO mice improved insulin sensitivity in the recipient mice. Mechanistically, circulating FGF-21 acts in an endocrine manner on subcutaneous fat to promote the healthy expansion. FGF-21 upregulates adiponectin in subcutaneous adipose tissue, accompanied with an increase of M2 macrophage polarization. This study raises the possibility that targeting subcutaneous fat through manipulation of FGF-21 may represent a promising therapeutics to combat insulin resistance. Disclosure H. Li: None. L. Qian: None. L. Wu: None.

Pituitary Macroprolactinoma with Mildly Elevated Serum Prolactin: Hook Effect.

A 45-year-old man was admitted in our department with complaints of severe headache for over 6 months period. He also suffered from several problems such as visual field defect, decreased energy and libido, body hair loss, cold intolerance, decreased appetite and dry skin. On physical examination, he was afebrile: BP (blood pressure): 110/70 mm/Hg, PR (pulse rate) :65 beat/min, BMI (body mass index): 24. He had no terminal hair on face or chest and subcutaneous adipose tissue mass had been decreased substantially. Laboratory tests revealed; Hb: 12 g/dL (N: 14–17 g/dL), Total testosterone: 1.2 ng/mL (N:–-10 ng/mL), Luteinizing hormone (LH):3.3MIU/mL (N:1–8 MIU/mL), Follicle Stimulating hormone (FSH):1.3 MIU/mL (N:1–7 MIU/mL), T4:3.4 micg/dL (N:4–12 micg/dL), TSH:0.6 MIU/mL (N:0.5–5 MIU/mL), Prolactin:100 ng/mL (2–24 ng/mL), serum cortisol:6 MIU/mL (N:4–21 MIU/mL), IGF1:162 ng/mL (50–245). Pituitary MRI showed macroadenoma (29*16*14 mm) in left side of sella turcica which bulged to suprasellar cistern with pressure effect on left optic nerve (Figure 1, 2). Visual field examination revealed mild temporal hemianopia. These findings are consistent with macroadenoma and mild prolactin elevation. We also observed a discrepancy between pituitary tumor size and prolactin level. The correct estimate of serum prolactin was obtained after serial dilutional measurement. Serum prolactin after dilution was 6470 ng/mL. With these findings pituitary macroadenoma was diagnosed and treatment with cabergoline (dopamine agonist) 0.5 mg/week was started. After one month follow-up he had no symptoms, visual field defect was improved and pituitary MRI showed significant shrinkage of tumor.

Low-Dose d-Amphetamine Induced Regression of Liver Fat Deposits in Dercum Disease

BackgroundDercum disease is a rare disorder of painful subcutaneous adipose tissue masses typically presenting as a constellation of signs and symptoms affecting most organs, including slow lymphatic flow and fatty liver. MethodThe University of Arizona Institutional Review Board considered this report exempt after patient consent. Multislice, multisequence magnetic resonance imaging (MRI) of the abdomen and pelvis was performed prior to and after d-amphetamine, with and without intravenous gadolinium. ResultsInitial MRI demonstrated hepatic steatosis in Case 1; Case 2 had 2-subcentimeter lipid foci within the liver. Initiation of 10-20 mg d-amphetamine decreased liver lipid deposition from 16% to 4% in Case 1 and resolved fat deposits in Case 2 after ~1 year. ConclusionThere is a dire need for novel treatment options for nonalcoholic fatty liver disease to prevent progression to cirrhosis. Reduction of liver fat by d-amphetamine suggests a potential therapeutic role in nonalcoholic fatty liver disease.

The Diabetes Gene and Wnt Pathway Effector TCF7L2 Regulates Adipocyte Development and Function.

The gene encoding for transcription factor 7-like 2 (TCF7L2) is the strongest type 2 diabetes mellitus (T2DM) candidate gene discovered to date. The TCF7L2 protein is a key transcriptional effector of the Wnt/β-catenin signaling pathway, which is an important developmental pathway that negatively regulates adipogenesis. However, the precise role that TCF7L2 plays in the development and function of adipocytes remains largely unknown. Using a combination of in vitro approaches, we first show that TCF7L2 protein is increased during adipogenesis in 3T3-L1 cells and primary adipocyte stem cells and that TCF7L2 expression is required for the regulation of Wnt signaling during adipogenesis. Inactivation of TCF7L2 protein by removing the high-mobility group (HMG)-box DNA binding domain in mature adipocytes in vivo leads to whole-body glucose intolerance and hepatic insulin resistance. This phenotype is associated with increased subcutaneous adipose tissue mass, adipocyte hypertrophy, and inflammation. Finally, we demonstrate that TCF7L2 mRNA expression is downregulated in humans with impaired glucose tolerance and adipocyte insulin resistance, highlighting the translational potential of these findings. In summary, our data indicate that TCF7L2 has key roles in adipose tissue development and function that may reveal, at least in part, how TCF7L2 contributes to the pathophysiology of T2DM.

Decreased lipogenesis-promoting factors in adipose tissue in postmenopausal women with overweight on a Paleolithic-type diet

PurposeWe studied effects of diet-induced postmenopausal weight loss on gene expression and activity of proteins involved in lipogenesis and lipolysis in adipose tissue.MethodsFifty-eight postmenopausal women with overweight (BMI 32.5 ± 5.5) were randomized to eat an ad libitum Paleolithic-type diet (PD) aiming for a high intake of protein and unsaturated fatty acids or a prudent control diet (CD) for 24 months. Anthropometry, plasma adipokines, gene expression of proteins involved in fat metabolism in subcutaneous adipose tissue (SAT) and lipoprotein lipase (LPL) activity and mass in SAT were measured at baseline and after 6 months. LPL mass and activity were also measured after 24 months.ResultsThe PD led to improved insulin sensitivity (P < 0.01) and decreased circulating triglycerides (P < 0.001), lipogenesis-related factors, including LPL mRNA (P < 0.05), mass (P < 0.01), and activity (P < 0.001); as well as gene expressions of CD36 (P < 0.05), fatty acid synthase, FAS (P < 0.001) and diglyceride acyltransferase 2, DGAT2 (P < 0.001). The LPL activity (P < 0.05) and gene expression of DGAT2 (P < 0.05) and FAS (P < 0.05) were significantly lowered in the PD group versus the CD group at 6 months and the LPL activity (P < 0.05) remained significantly lowered in the PD group compared to the CD group at 24 months.ConclusionsCompared to the CD, the PD led to a more pronounced reduction of lipogenesis-promoting factors in SAT among postmenopausal women with overweight. This could have mediated the favorable metabolic effects of the PD on triglyceride levels and insulin sensitivity.

Schisandrin B regulates lipid metabolism in subcutaneous adipocytes

Subcutaneous adipocytes in obese subjects have a lower sensitivity to catecholamine-induced lipolysis and a higher sensitivity to insulin anti-lipolytic effects compared to adipocytes in other adipose depots. Therefore, increasing lipolysis in subcutaneous adipocytes coupled with enhanced fatty acid oxidation may be an anti-obesity strategy. Schisandrin B (Sch B) is one of the most abundant active dibenzocyclooctadiene derivatives found in the fruit of Schisandra chinensis which is a commonly prescribed Chinese medicinal herb. We found that Sch B reduced glycerolipid contents in 3T3-L1 adipocytes and subcutaneous adipocytes dissected from DIO mice. Sch B also activated hormone sensitive lipase (HSL) and increased lipolysis in these adipocyte in a protein kinase A-dependent manner. Interestingly, Sch B increased fatty acid oxidation gene expressions in these adipocytes, implying an increase in fatty acid oxidation after treatment. In in vivo model, we found that Sch B increased HSL phosphorylation, reduced glycerolipid levels and increased fatty acid oxidation gene expressions in the subcutaneous adipocytes in the DIO mice. More importantly, Sch B significantly reduced the subcutaneous adipocyte sizes, subcutaneous adipose tissue mass and body weight of the mice. Our study provides scientific evidence to suggest a potential therapeutic function of Sch B or Schisandra chinensis seed containing Sch B in reducing obesity.

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.

Ovarian hormones and obesity.

Obesity is caused by an imbalance between energy intake, i.e. eating and energy expenditure (EE). Severe obesity is more prevalent in women than men worldwide, and obesity pathophysiology and the resultant obesity-related disease risks differ in women and men. The underlying mechanisms are largely unknown. Pre-clinical and clinical research indicate that ovarian hormones may play a major role. We systematically reviewed the clinical and pre-clinical literature on the effects of ovarian hormones on the physiology of adipose tissue (AT) and the regulation of AT mass by energy intake and EE. Articles in English indexed in PubMed through January 2016 were searched using keywords related to: (i) reproductive hormones, (ii) weight regulation and (iii) central nervous system. We sought to identify emerging research foci with clinical translational potential rather than to provide a comprehensive review. We find that estrogens play a leading role in the causes and consequences of female obesity. With respect to adiposity, estrogens synergize with AT genes to increase gluteofemoral subcutaneous AT mass and decrease central AT mass in reproductive-age women, which leads to protective cardiometabolic effects. Loss of estrogens after menopause, independent of aging, increases total AT mass and decreases lean body mass, so that there is little net effect on body weight. Menopause also partially reverses women's protective AT distribution. These effects can be counteracted by estrogen treatment. With respect to eating, increasing estrogen levels progressively decrease eating during the follicular and peri-ovulatory phases of the menstrual cycle. Progestin levels are associated with eating during the luteal phase, but there does not appear to be a causal relationship. Progestins may increase binge eating and eating stimulated by negative emotional states during the luteal phase. Pre-clinical research indicates that one mechanism for the pre-ovulatory decrease in eating is a central action of estrogens to increase the satiating potency of the gastrointestinal hormone cholecystokinin. Another mechanism involves a decrease in the preference for sweet foods during the follicular phase. Genetic defects in brain α-melanocycte-stimulating hormone-melanocortin receptor (melanocortin 4 receptor, MC4R) signaling lead to a syndrome of overeating and obesity that is particularly pronounced in women and in female animals. The syndrome appears around puberty in mice with genetic deletions of MC4R, suggesting a role of ovarian hormones. Emerging functional brain-imaging data indicates that fluctuations in ovarian hormones affect eating by influencing striatal dopaminergic processing of flavor hedonics and lateral prefrontal cortex processing of cognitive inhibitory controls of eating. There is a dearth of research on the neuroendocrine control of eating after menopause. There is also comparatively little research on the effects of ovarian hormones on EE, although changes in ovarian hormone levels during the menstrual cycle do affect resting EE. The markedly greater obesity burden in women makes understanding the diverse effects of ovarian hormones on eating, EE and body adiposity urgent research challenges. A variety of research modalities can be used to investigate these effects in women, and most of the mechanisms reviewed are accessible in animal models. Therefore, human and translational research on the roles of ovarian hormones in women's obesity and its causes should be intensified to gain further mechanistic insights that may ultimately be translated into novel anti-obesity therapies and thereby improve women's health.

Amelioration of fatty liver index in patients with type 2 diabetes on ipragliflozin: an association with glucose-lowering effects.

In this study, we investigated the ameliorating effects of ipragliflozin on fatty liver in patients with type 2 diabetes. The factors that influenced the amelioration of fatty liver were also examined. Analysis included data of 21 Japanese patients with type 2 diabetes obtained from our prospective observational study. After obtaining patients' informed consent, once-daily ipragliflozin (50 mg/day) was given for 16 weeks. In addition to several clinical parameters, body composition was also compared before and after 16 weeks of treatment. The extent of fatty liver was estimated using a fatty liver index (FLI). After 16 weeks, FLI significantly decreased, from 70.1 ± 19.4 to 60.3 ± 25.5 (p = 0.0009) as well as levels of fasting plasma glucose (FPG), HbA1c, body weight, visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and fat mass. To reveal the factors influencing the FLI changes observed on ipragliflozin treatment, correlations between changes in FLI and several other measured parameters were examined. Changes in FPG (correlation coefficient = 0.4683, p = 0.0323) and HbA1c (correlation coefficient = 0.4383, p = 0.0469) showed significant positive correlations with changes in FLI. On the other hand, no correlations of changes in FLI were observed with body weight, VAT, SAT nor fat mass. In conclusion, ipragliflozin ameliorated FLI in Japanese patients with type 2 diabetes. Improvement in FLI was associated with that of glucose intolerance.

Habitual physical activity protects against lipopolysaccharide-induced inflammation in mouse adipose tissue

ABSTRACTSepsis is a systemic inflammatory response to infection, with no preventative strategies. In this study, we identify a role for habitual physical activity in the prevention of adipose tissue inflammation induced by a model of sepsis, lipopolysaccharide (LPS). Male C57BL/6J mice (8 weeks old) were housed with access to voluntary wheel running (VWR) or sedentary (SED) for 10 weeks. Mice were then injected with LPS (2 mg/kg) or saline (SAL), and tissues were removed 6 hours post-injection. VWR attenuated body, epididymal adipose tissue (eWAT), and subcutaneous inguinal adipose tissue (iWAT) mass gain, improved glucose tolerance, increased markers of mitochondrial biogenesis in iWAT and eWAT, and increased UCP-1 protein content in iWAT. In iWAT, VWR attenuated the LPS induced increase in mRNA expression of TNF-α, MCP-1, and follistatin, along with phosphorylation of STAT3. In addition, VWR had a main effect for reducing iWAT mRNA expression of IL-1β, IL-6, and SOCS3. In eWAT, VWR had a main effect for reducing mRNA expression of IL-1β, MCP-1, IL-6, and follistatin. Further, VWR increased SOCS3 mRNA expression and phosphorylation of STAT3 in SAL mice, thus the relative change in response to LPS for these markers was attenuated. The protective effect of prior physical activity occurred in conjunction with increases in the protein content of a component of the LPS binding complex, MyD88. Overall, the results from this study demonstrate that habitual physical activity can attenuate the LPS induced inflammatory response in adipose tissue and this occurs to a greater extent in iWAT compare with eWAT.

Biomarkers of browning of white adipose tissue and their regulation during exercise- and diet-induced weight loss ,

Background: A hypothesis exists whereby an exercise- or dietary-induced negative energy balance reduces human subcutaneous white adipose tissue (scWAT) mass through the formation of brown-like adipocyte (brite) cells. However, the validity of biomarkers of brite formation has not been robustly evaluated in humans, and clinical data that link brite formation and weight loss are sparse.Objectives: We used rosiglitazone and primary adipocytes to stringently evaluate a set of biomarkers for brite formation and determined whether the expression of biomarker genes in scWAT could explain the change in body composition in response to exercise training combined with calorie restriction in obese and overweight women (n = 79).Design: Gene expression was derived from exon DNA microarrays and preadipocytes from obesity-resistant and -sensitive mice treated with rosiglitazone to generate candidate brite biomarkers from a microarray. These biomarkers were evaluated against data derived from scWAT RNA from obese and overweight women before and after supervised exercise 5 d/wk for 16 wk combined with modest calorie restriction (∼0.84 MJ/d).Results: Forty percent of commonly used brite gene biomarkers exhibited an exon or strain-specific regulation. No biomarkers were positively related to weight loss in human scWAT. Greater weight loss was significantly associated with less uncoupling protein 1 expression (P = 0.006, R2 = 0.09). In a follow-up global analysis, there were 161 genes that covaried with weight loss that were linked to greater CCAAT/enhancer binding protein α activity (z = 2.0, P = 6.6 × 10−7), liver X receptor α/β agonism (z = 2.1, P = 2.8 × 10−7), and inhibition of leptin-like signaling (z = −2.6, P = 3.9 × 10−5).Conclusion: We identify a subset of robust RNA biomarkers for brite formation and show that calorie-restriction–mediated weight loss in women dynamically remodels scWAT to take on a more-white rather than a more-brown adipocyte phenotype.

Circulating leptin and NF-κB activation in peripheral blood mononuclear cells across the menstrual cycle.

Using the menstrual cycle as a model, this study focused on longitudinal changes and associations within a physiological network known to play a role in female fertility, including, as biologically active nodes, NF-κB, leptin and adiponectin, β-carotene, adipose tissue, and progesterone. In 28 women, leptin, adiponectin, β-carotene, and progesterone concentrations, NF-κB p65 and p50 activation in peripheral blood mononuclear cells (known to possess estrogen, progesterone and leptin receptors), total body fat (TBF) and subcutaneous adipose tissue (SAT) mass were determined at early (T1) and late follicular (T2) and mid (T3) and late (T4) luteal phase. Leptin and adiponectin concentrations were higher, while NF-κB p65 activation was lower at T3 compared with T1. NF-κB p65 activation was inversely related to leptin concentrations at T1, T3, and T4. β-Carotene was inversely related to leptin (T1,T2,T4) and SAT (T1,T3,T4). NF-κB p50 activation was inversely related to TBF (T4) and SAT (T3,T4), and leptin was positively related to TBF and SAT (T1-T4). Progesterone was inversely related to leptin (T2,T3), adiponectin (T3), TBF (T3,T4), and SAT (T2,T3,T4). By providing evidence of luteal phase-specific reduced NF-κB p65 activation in women under physiological conditions, this study bridges the gap between existing evidence of a Th1-Th2 immune response shift induced by reduced NF-κB p65 activation and a Th1-Th2 shift previously observed at luteal phase. For the first time, inverse regressions suggest inhibitory effects of leptin on NF-κB p65 activation at luteal phase, along with inhibitory effects of leptin as well as adiponectin on progesterone production in corpus luteum. © 2016 The Authors BioFactors published by Wiley Periodicals, Inc. on behalf of International Union of Biochemistry and Molecular Biology. 24(4):376-387, 2016.

Decreased beige adipocyte number and mitochondrial respiration coincide with reduced FGF21 gene expression in Sprague Dawley rats fed prenatal low protein and postnatal high fat diets

We have shown that protein malnutrition during fetal growth followed bypostnatal high‐fat diets results in a rapid increase in subcutaneous adiposetissue mass in the offspring contributing to development of obesity and insulin resistance. Recent studies have shown that the absence of a key transcription factor PR domain containing 16 (PRDM16) and fibroblast growth factor 21 (FGF21)are involved in conversion of precursor white adipocytes into more mitochondrial enriched and metabolically active beige adipocytes cause marked enlargement of the subcutaneous adipose tissue. Our hypothesis is that amaternal LP and postnatal HF diets increase the risk of development of obesity and insulin resistance in offspring, in part, by reducing the conversion of precursor white adipocytes into beige adipocytes in the subcutaneous adiposetissue of offspring. Using obese‐prone Sprague‐Dawley rats fed 8% low protein(LP) or 20% normal protein (NP) diets for 3 wk prior to conception and throughout pregnancy and lactation followed by 12 wks of 10% normal fat (NF) or 45% high fat (HF) diet feeding, we investigated whether prenatal LP and postnatal HF diets affect beige adipocyte number and oxidative respiratory function in subcutaneous adipose tissue. Results showed that subcutaneous adipose and liver fibroblast growth factor 21 (FGF21), PRDM16, and beigeadipocyte marker CD137, mRNA increase with postnatal HF diet in maternal NP group mice. In contrast, mice fed maternal LP and postnatal HF diets showed no increase in subcutaneous adipose tissue mitochondrial copy number, oxygen consumption rate, FGF21, PRDM16, and CD137 mRNA. These findings suggest that high‐fat diet fed offspring from mothers that consumed a low‐protein diet have reduced induction of beige adipocytes in subcutaneous adipose tissue and that this may be part of the mechanism by which maternal protein malnutrition causes offspring obesity and metabolic alterations.Support or Funding InformationThis work was supported by USDA Agricultural Research Service Project #3062‐51000‐052‐00D.

Regulation of Metabolism by Estrogen Receptor Alpha

Postmenopausal estrogen deficiency increases the risk for metabolic syndrome, obesity, and type 2 diabetes. Estrogen treatment improves metabolic function in postmenopausal women, and estrogen receptor α (ERα) is thought to be the primary player in these protective metabolic effects. However, the mechanisms behind ERα regulation of metabolic function have not been elucidated. The purpose of this study was to investigate the impact of ERα loss on whole body and skeletal muscle oxidative capacity in a rat model. 14 wk‐old female Wildtype (WT) and ERα knockout (ERα−/−) rats were exercised to exhaustion and one week later a glucose tolerance test was performed. At sacrifice, body weight and adipose tissue depot weights (subcutaneous, retroperitoneal and periuterine) were measured. Adipocyte cell size and mitochondrial protein content were assessed by immunohistochemistry and western blot, respectively. Intramuscular triglyceride storage was also assessed. ERα deficient rats had increased body weight and subcutaneous adipose tissue mass compared with WT rats. Although there was no increase in retroperitoneal adipose tissue mass, adipocyte size was increased in ERα deficient rats. HOMA‐IR values were also increased in ERα−/− animals indicating increased insulin resistance. ERα deficiency also decreased exercise time to exhaustion when compared with WT rats. Mitochondrial proteins Complex IV and peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PGC1α) were significantly decreased and intramuscular triglyceride storage was increased in skeletal muscles from ERα deficient rats. Our data demonstrate the potential regulatory role of ERα to enhance oxidative capacity and improve energy metabolism both systemically and in skeletal muscle. Pharmacological activation of ERα could be an effective strategy for the prevention and treatment of metabolic dysfunction. Selective estrogen receptor modulators currently used as treatment for various postmenopausal symptoms may have the potential to restore metabolic function in postmenopausal women and improve quality of life.Support or Funding InformationThis research was supported in part by an NIH grant (R01 AG031575) and the IRHRM Pilot grant.

Abstract P289: Sex Differences in the Rate of Visceral Adipose Tissue Accrual During Adulthood

Introduction: Excess visceral adipose tissue (VAT) robustly predicts incident cardiometabolic risk, independent of body mass index (BMI), and this association is stronger in women than in men. Cross-sectional studies suggest that VAT accrual accelerates in older women as compared to similarly aged men, in concert with menopausal changes, which may help to explain the greater effect of VAT on subsequent disease risk observed in women. However, a direct test of sex differences in the rate of VAT accrual requires longitudinal VAT data which have been largely lacking. Objectives: This analysis evaluated sex differences in the rate of VAT accrual in adults. Secondary analyses examined differences in the rate of VAT accrual in pre-, peri-, and post-menopausal women. Methods: Participants were 532 (59% female) non-Hispanic white adults, aged 18-84 years at baseline, who were enrolled in a study of normative changes in body composition over the lifespan. Abdominal VAT mass and subcutaneous adipose tissue (SAT) mass were assessed using multiple-image magnetic resonance imaging at two time points, with an average follow-up of 7.2 ± 2.5 years. Linear regression models were used to examine the effects of sex, baseline age, and their interaction on rate of change per year in body composition measures (ΔBMI, ΔVAT, and ΔVAT/SAT ratio (ΔVSR)) independent of baseline body composition measures and baseline visit year. Secondary analyses examined differences in these rates of change by baseline menopausal status (pre, peri, post), after adjustment for baseline age. Results: Levels of BMI, VAT, and VSR all increased over the follow-up period on average; however, the change in BMI (mean ΔBMI = +0.5%) was far smaller than for VAT (mean ΔVAT=+6.3%) and VSR (mean ΔVSR = +3.4%). ΔVAT and ΔBMI decreased linearly with age in both sexes (p&lt;0.001), such that older individuals had lower rates of VAT and BMI gain, and this deceleration in VAT and BMI accrual was greater in men than women (p for interaction 0.007 and 0.038, respectively). ΔVSR did not vary with age in either sex, but remained higher in men than women throughout adulthood. ΔBMI, ΔVAT, and ΔVSR did not differ by baseline menopausal status. Conclusions: VAT mass increased with age in both men and women, but the rate of VAT gain gradually declined with advancing age. There was no evidence of accelerated VAT accrual during menopause as previously reported in the literature. However, the rate of VAT gain was more consistent in women during adulthood than in men, who exhibited greater deceleration. Future work will explore whether this sex difference in the pattern of body composition change explains the differential effects of VAT on disease risk in men and women.

Decreased beige adipocyte number and mitochondrial respiration coincide with increased histone methyl transferase (G9a) and reduced FGF21 gene expression in Sprague–Dawley rats fed prenatal low protein and postnatal high-fat diets

We have shown that prenatal low-protein (LP) followed by postnatal high-fat (HF) diets result in a rapid increase in subcutaneous adipose tissue (subc-AT) mass in the offspring, contributing to development of obesity and insulin resistance. Studies have shown that a key transcription factor, PR domain containing 16 (PRDM16), and fibroblast growth factor 21 (FGF21) are involved in conversion of precursor cells into mitochondria (mt)-enriched beige adipocytes (BA). Our hypothesis is that a maternal LP and postnatal HF diets increase the risk of obesity and insulin resistance in offspring, in part, by reducing the conversion of precursor cell into BA in the subc-AT of offspring. Using obese-prone Sprague–Dawley rats fed 8% LP or 20% normal-protein (NP) diets for 3 weeks prior to conception and throughout pregnancy and lactation followed by 12 weeks of 10% normal-fat (NF) or 45% HF diet feeding, we investigated whether prenatal LP and postnatal HF diets affect BA number and oxidative respiratory function in subc-AT. Results showed that subc-AT and liver FGF21, PRDM16 and BA marker CD137 mRNA increase with postnatal HF diet in maternal NP group rats. In contrast, rats fed maternal LP and postnatal HF diets showed no increase in subc-AT mt copy number, oxygen consumption rate, FGF21, PRDM16 and CD137 mRNA, whereas protein expression of an inhibitor for FGF21 transcription (histone methyltransferase, G9a) increased. These findings suggest that LPHF diets cause offspring metabolic alterations by reduced BA and FGF21 mRNA and increased G9a protein expression in subc-AT.