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Context In rodents, cold exposure induces the activation of brown adipose tissue (BAT) and the induction of intracellular triacylglycerol (TAG) lipolysis. However, in humans, the kinetics of supraclavicular (SCV) BAT activation and the potential importance of TAG stores remain poorly defined. Objective To determine the time course of BAT activation and changes in intracellular TAG using MRI assessment of the SCV (i.e., BAT depot) and fat in the posterior neck region (i.e., non-BAT). Design Cross-sectional. Setting Clinical research center. Patients or Other Participants Twelve healthy male volunteers aged 18 to 29 years [body mass index = 24.7 ± 2.8 kg/m2 and body fat percentage = 25.0% ± 7.4% (both, mean ± SD)]. Intervention(s) Standardized whole-body cold exposure (180 minutes at 18°C) and immediate rewarming (30 minutes at 32°C). Main Outcome Measure(s) Proton density fat fraction (PDFF) and T2* of the SCV and posterior neck fat pads. Acquisitions occurred at 5- to 15-minute intervals during cooling and subsequent warming. Results SCV PDFF declined significantly after only 10 minutes of cold exposure [−1.6% (SE: 0.44%; P = 0.007)] and continued to decline until 35 minutes, after which time it remained stable until 180 minutes. A similar time course was also observed for SCV T2*. In the posterior neck fat (non-BAT), there were no cold-induced changes in PDFF or T2*. Rewarming did not result in a change in SCV PDFF or T2*. Conclusions The rapid cold-induced decline in SCV PDFF suggests that in humans BAT is activated quickly in response to cold and that TAG is a primary substrate.

Zinc finger factors are implicated in a variety of cellular processes, including adipose tissue differentiation and thermogenesis. We have previously demonstrated that zinc finger protein 638 (ZNF638) is a transcriptional coactivator acting as an early regulator of adipogenesis in vitro. In this study, we show, to our knowledge for the first time, that, in vivo, ZNF638 abounds selectively in mature brown and subcutaneous fat tissues and in fully differentiated thermogenic adipocytes. Furthermore, gene expression studies revealed that ZNF638 is upregulated by cAMP modulators in vitro and by cold exposure and by pharmacological stimulation of β-adrenergic signaling in vivo. In silico analysis of the upstream regulatory region of the ZNF638 gene identified two putative cAMP response elements within 500 bp of the ZNF638 transcription start site. Detailed molecular analysis involving EMSA and chromatin immunoprecipitation assays demonstrated that cAMP response element binding protein (CREB) binds to these cAMP response element regions of the ZNF638 promoter, and functional studies revealed that CREB is necessary and sufficient to regulate the levels of ZNF638 transcripts. Taken together, these results demonstrate that ZNF638 is selectively expressed in mature thermogenic adipocytes and tissues and that its induction in response to classic stimuli that promote heat generation is mediated via CREB signaling, pointing to a possible novel role of ZNF638 in brown and beige fat tissues.

The interaction between thyroid status and brown adipose tissue (BAT) activation is complex. We assessed the effect of autoimmune hypothyroidism (ATD) in female children on BAT activation, measured using infrared thermography. Participants with ATD had lower resting (hypothyroid, 34.9 +- 0.7°C; control, 35.4 +- 0.5°C; P = 0.03) and stimulated (hypothyroid, 35.0 +- 0.6°C; control, 35.5 +- 0.5°C; P = 0.04) supraclavicular temperatures compared with controls, but there was no difference between groups in the temperature increase with stimulation. BAT activation, calculated as the relative temperature change comparing the supraclavicular temperature to a sternal reference region, was reduced in participants with ATD (hypothyroid, 0.1 +- 0.1°C; control, 0.2 +- 0.2°C; P = 0.04). Children with ATD were frequently biochemically euthyroid due to replacement therapy, but, despite this, increased relative supraclavicular temperature was closely associated with increased TSH (r = 0.7, P = 0.01) concentrations. Girls with ATD had an attenuated thermogenic response to cold stimulation compared with healthy controls, but, contrary to expectation, those with suboptimal biochemical control (with higher TSH) showed increased BAT activation. This suggests that the underlying disease process may have a negative effect on BAT response, but high levels of TSH can mitigate, and even stimulate, BAT activity. In summary, thyroid status is a complex determinant of BAT activity in girls with ATD., This work was supported by a pump-priming grant from Nottingham University Hospitals Charity (Grant PP-Law-Nov12).

Bisphenol A (BPA) has been recognized as an endocrine disrupting chemical and identified as an obesogen. Although once ubiquitous, human exposure to BPA has been declining owing to its substitution with other bisphenols. Two structurally similar substitutes, bisphenol S (BPS) and bisphenol F (BPF), have raised similar concerns, although fewer studies have been conducted on these newer derivatives. We used data from the US National Health and Nutrition Examination Surveys from 2013 to 2016 to evaluate associations between BPA, BPS, and BPF and body mass outcomes among children and adolescents aged 6 to 19 years. Concentrations of BPA, BPS, and BPF were measured in spot urine samples using HPLC with tandem mass spectrometry. General obesity was defined as ≥95th percentile of the age- and sex-standardized body mass index (BMI) z-scores according to the 2000 US norms. Abdominal obesity was defined as a waist circumference/height ratio of ≥0.5. BPA, BPS, and BPF were detected in 97.5%, 87.8%, and 55.2% of urine samples, respectively. Log-transformed urinary BPS concentrations were associated with an increased prevalence of general obesity (OR, 1.16; 95% CI, 1.02 to 1.32) and abdominal obesity (OR, 1.13; 95% CI, 1.02 to 1.27). BPF detection (vs not detected) was associated with an increased prevalence of abdominal obesity (OR, 1.29; 95% CI, 1.01 to 1.64) and continuous BMI z-score (β = 0.10; 95% CI, 0.01 to 0.20). BPA and total bisphenols were not statistically significantly associated with general obesity, abdominal obesity, or any body mass outcome. These results suggest that BPA substitute chemicals are correlated with obesity in contemporary children.

Hyperinsulinemia is strongly associated with type 2 diabetes. Racial and ethnic minority populations are disproportionately affected by diabetes and obesity-related complications. This mini-review provides an overview of the genetic and environmental factors associated with hyperinsulinemia with a focus on racial and ethnic differences and its metabolic consequences. The data used in this narrative review were collected through research in PubMed and reference review of relevant retrieved articles. Insulin secretion and clearance are regulated processes that influence the development and progression of hyperinsulinemia. Environmental, genetic, and dietary factors are associated with hyperinsulinemia. Certain pharmacotherapies for obesity and bariatric surgery are effective at mitigating hyperinsulinemia and are associated with improved metabolic health. Hyperinsulinemia is associated with many environmental and genetic factors that interact with a wide network of hormones. Recent studies have advanced our understanding of the factors affecting insulin secretion and clearance. Further basic and translational work on hyperinsulinemia may allow for earlier and more personalized treatments for obesity and metabolic diseases.

Context The gut microbiome is a source of inflammatory factors such as lipopolysaccharide (LPS; endotoxin) that influence metabolic homeostasis. Rifaximin is a well-tolerated antibiotic that may reduce LPS. Objective We sought to develop a method to accurately assess postprandial endotoxemia and to determine whether rifaximin treatment improves metabolic homeostasis in obese humans with metabolic syndrome. Design and Setting Plasma LPS, adipose inflammation, glucose and lipid metabolism, and insulin sensitivity were evaluated in a clinical research setting. Participants Twelve obese human research participants with prediabetes or three features of metabolic syndrome participated. Intervention The research participants were randomized to placebo control or rifaximin soluble solid dispersion (80 mg/d) treatment groups and treated for 12 weeks. Outcome Measures We evaluated changes in insulin sensitivity with a euglycemic clamp; changes in lipid and glucose metabolism with oral lipid and glucose tolerance tests; changes in plasma LPS during the lipid tolerance test; and changes in adipose tissue and systemic inflammation by measuring inflammatory cytokines. Results Rifaximin treatment slightly worsened insulin sensitivity (P = 0.03), did not improve glucose or lipid homeostasis, and did not significantly improve adipose tissue inflammation. Our efforts to accurately assess plasma LPS using limulus amebocyte lysate assays revealed that the majority of LPS is masked from detection by limulus amebocyte lysate assays, but can be unmasked using a pretreatment step with protease. Unmasked LPS increases during the lipid tolerance test, but rifaximin treatment did not reduce this. Conclusions Rifaximin treatment did not lower plasma LPS or improve metabolic homeostasis in obese humans.

Postprandial hyperinsulinemic hypoglycemia is an uncommon yet well-established complication of Roux-en-Y gastric bypass (RYGB) that can result in serious morbidity and adversely affect quality of life. It is often unrecognized and may be difficult to diagnose. Management is challenging. As the number of bariatric procedures increases in parallel with the obesity epidemic, clinicians will be tasked to offer effective medical therapies for this complication. Two patients presented several years after RYGB with severe postprandial hypoglycemia. In one of the patients, we were able to document simultaneous postprandial hypoglycemia and hyperinsulinemia. Conventional treatment approaches, including medical nutrition therapy, acarbose, diazoxide, and octreotide, were either ineffective or limited by poor tolerance. Nifedipine and verapamil were used adjunctively with dietary modification, resulting in resolution of symptomatic hypoglycemic episodes. These agents are therapeutic options that can be used for some patients refractory to more traditional treatments. They should be tried before surgical procedures are considered for affected patients. These two cases demonstrate that calcium channel blockers may be efficacious and appropriate for select patients refractory to dietary interventions alone.

Mice with a targeted mutation in the pro-opiomelanocortin (Pomc) gene (Pomctm1/tm1 mice) are unable to synthesize desacetyl-α-MSH and α-MSH and they develop obesity when fed chow diet. In this study, we hypothesized that a chronic high-fat (HF) diet exacerbates Pomctm1/tm1 mouse obesity. Male and female Pomcwt/wt and Pomctm1/tm1 mice were fed low-fat (LF) (10 kcal percent fat) or HF (45 kcal percent fat) diets from weaning for 23 weeks. We show that Pomctm1/tm1 mouse obesity is sexually dimorphic and exacerbated by an HF diet. Male Pomctm1/tm1 mice develop obesity because they are hyperphagic compared with Pomcwt/wt mice when fed an LF or HF diet. Female Pomctm1/tm1 mice develop obesity when feeding on an LF or HF diet because they exhibit signs of reduced energy expenditure (no change in feed efficiency; body weight gained exceeding energy intake) compared with Pomcwt/wt mice. A chronic HF diet exacerbates male Pomctm1/tm1 and Pomcwt/wt mouse obesity, and the increased energy intake fully accounts for increased weight gain. In contrast, female Pomcwt/wt mice are protected from chronic HF diet–induced obesity because they reduce the amount of HF diet eaten, and they appear to increase their energy expenditure (no change in feed efficiency but energy intake exceeding body weight gained). A chronic HF diet exacerbates female Pomctm1/tm1 mouse obesity due to impaired ability to reduce the amount of HF diet eaten and apparent impaired HF diet–induced adaptive thermogenesis. Our data show that desacetyl-α-MSH and α-MSH are required for sexually dimorphic HF diet–induced C57BL/6J obesity. In conclusion, desacetyl-α-MSH and α-MSH play salutary roles in sexually dimorphic melanocortin obesity and sexually dimorphic HF diet–induced C57BL/6J obesity.

Both fibroblast growth factors (FGFs), by binding to FGF receptors (FGFRs), and activation of the gravitostat, by artificial loading, decrease the body weight (BW). Previous studies demonstrate that both the FGF system and loading have the capacity to regulate BW independently of leptin. The aim of the current study was to determine the possible interactions between the effect of increased loading and the FGF system for the regulation of BW. We observed that the BW-reducing effect of increased loading was abolished in mice treated with a monoclonal antibody directed against FGFR1c, suggesting interactions between the two systems. As serum levels of endocrine FGF21 and hepatic FGF21 mRNA were increased in the loaded mice compared with the control mice, we first evaluated the loading response in FGF21 over expressing mice with constant high FGF21 levels. Leptin treatment, but not increased loading, decreased the BW in the FGF21-overexpressing mice, demonstrating that specifically the loading effect is attenuated in the presence of high activity in the FGF system. However, as FGF21 knockout mice displayed a normal loading response on BW, FGF21 is neither mediating nor essential for the loading response. In conclusion, the BW-reducing effect of increased loading but not of leptin treatment is blocked by high activity in the FGF system. We propose that both the gravitostat and the FGF system regulate BW independently of leptin and that pharmacologically enhanced activity in the FGF system reduces the sensitivity of the gravitostat.

Context Vitamin D plays a role in the differentiation and metabolism of skeletal muscle and, possibly, adipose tissue; however, the relationship between vitamin D status during growth and body composition in early adulthood is unclear. Objective We examined associations between vitamin D status in childhood, adolescence, and early adulthood with body composition at age 20 years. Design, Setting, Participants We studied 821 offspring (385 females) of the Western Australian Pregnancy Cohort Study who had ≥3 serum 25-hydroxyvitamin D [25(OH)D] at age 6, 14, 17, and 20 years and body composition assessed at age 20 using dual-energy x-ray absorptiometry. The participants were grouped into four vitamin D status trajectories: consistently lower, decreasing, increasing, and consistently higher. Results The mean serum 25(OH)D at the study visits was 72.7 to 86.8 nmol/L. In males, serum 25(OH)D at 17 and 20 years was positively associated with lean body mass (LBM), and 25(OH)D at age 20 correlated negatively with fat body mass (FBM). Males with a consistently higher 25(OH)D trajectory had a 2.3- to 3.7-kg greater LBM and 4.1- to 6.0-kg lower FBM at 20 years compared with those with consistently lower or decreasing trajectories (P < 0.05 for all). In females, 25(OH)D at 14, 17, and 20 years was negatively associated with FBM. Females with increasing or consistently higher 25(OH)D trajectories had a 5.2- to 6.8-kg lower FBM at age 20 compared with those with a consistently lower trajectory (P < 0.05 for all). Conclusions In the present predominantly white, relatively vitamin D-replete cohort, a higher vitamin D status trajectory from childhood to early adulthood was associated with a greater LBM in males and lower FBM in both sexes at age 20.

Emerging evidence indicates that ectopic skeletal muscle adiposity may be a risk factor for type 2 diabetes (T2D), especially in persons of African ancestry. In vitro studies suggest that a Wnt pathway inhibitor, Dickkopf-related protein 1 (DKK1), plays a role in adiposity regulation and could be a biomarker for adiposity in humans. The objective of this study was to test whether serum DKK1 levels relate to adiposity measures in a cohort from an African ancestry population at high risk for T2D. Fasting serum DKK1 was measured in a sample of 159 men of African ancestry aged ≥40 years (mean age ± SD, 63.5 ± 8.2 years; mean body mass index, 27.8 ± 4.5 kg/m2). Anthropometrics included total-body and trunk adiposity measured by dual-energy x-ray absorptiometry and lower-leg skeletal muscle density measured by CT [which reflects the intramuscular adiposity content (mg/cm3)]. Serum DKK1 was positively correlated with BMI (r = 0.20; P = 0.01), waist circumference (r = 0.15; P = 0.046), DXA total-body adiposity (r = 0.24; P = 0.003), and DXA trunk adiposity (r = 0.21; P = 0.009), independent of age and height. In addition, serum DKK1 was inversely correlated with skeletal muscle density (r = −0.25; P = 0.002), independent of age, BMI, and calf muscle area. No significant correlation was found between serum DKK1 and fasting serum glucose or insulin levels or insulin resistance estimated by homeostasis model assessment. These findings suggest that higher levels of serum DKK1 may be associated with greater overall, central, and ectopic skeletal muscle adiposity. Further studies are needed to unravel the potential role of DKK1 in the regulation of adiposity in humans.

The hypothalamic melanocortin system composed of proopiomelanocortin (POMC) and agouti-related protein (AgRP) neurons plays a key role in maintaining energy homeostasis. The POMC-derived peptides, α-MSH and β-EP, have distinct roles in this process. α-MSH inhibits food intake, whereas β-EP, an endogenous opioid, can inhibit POMC neurons and stimulate food intake. A mouse model was used to examine the effects of opioid antagonism with naltrexone (NTX) on Pomc and Agrp gene expression and POMC peptide processing in the hypothalamus in conjunction with changes in energy balance. There were clear stimulatory effects of NTX on hypothalamic Pomc in mice receiving low- and high-fat diets, yet only transient decreases in food intake and body weight gain were noted. The effects on Pomc expression were accompanied by an increase in POMC prohormone levels and a decrease in levels of the processed peptides α-MSH and β-EP. Arcuate expression of the POMC processing enzymes Pcsk1, Pcsk2, and Cpe was not altered by NTX, but expression of Prcp, an enzyme that inactivates α-MSH, increased after NTX exposure. NTX exposure also stimulated hypothalamic Agrp expression, but the effects of NTX on energy balance were not enhanced in Agrp-null mice. Despite clear stimulatory effects of NTX on Pomc expression in the hypothalamus, only modest transient decreases in food intake and body weight were seen. Effects of NTX on POMC processing, and possibly α-MSH inactivation, as well as stimulatory effects on AgRP neurons could mitigate the effects of NTX on energy balance.

Prolonged exposure to glucocorticoids (GCs) causes various metabolic derangements. These include obesity and insulin resistance, as inhibiting glucose utilization in adipose tissues is a major function of GCs. Although adipose tissue distribution and glucose homeostasis are sex-dependently regulated, it has not been evaluated whether GCs affect glucose metabolism and adipose tissue functions in a sex-dependent manner. In this study, high-dose corticosterone (rodent GC) treatment in C57BL/6J mice resulted in nonfasting hyperglycemia in male mice only, whereas both sexes displayed hyperinsulinemia with normal fasting glucose levels, indicative of insulin resistance. Metabolic testing using stable isotope-labeled glucose techniques revealed a sex-specific corticosterone-driven glucose intolerance. Corticosterone treatment increased adipose tissue mass in both sexes, which was reflected by elevated serum leptin levels. However, female mice showed more metabolically protective adaptations of adipose tissues than did male mice, demonstrated by higher serum total and high-molecular-weight adiponectin levels, more hyperplastic morphological changes, and a stronger increase in mRNA expression of adipogenic differentiation markers. Subsequently, in vitro studies in 3T3-L1 (white) and T37i (brown) adipocytes suggest that the increased leptin and adiponectin levels were mainly driven by the elevated insulin levels. In summary, this study demonstrates that GC-induced insulin resistance is more severe in male mice than in female mice, which can be partially explained by a sex-dependent adaptation of adipose tissues.

Context The NRLP3 inflammasome is a multiprotein danger-sensing complex that serves as a critical link between obesity-related adipose inflammation and insulin resistance and has been shown in animal models to be inhibited by fish oil-derived long chain omega-3 polyunsaturated fatty acids (n-3 PUFA). Objective We conducted a clinical trial and in vitro experiments to test our hypothesis that n-3 PUFA suppress NLRP3 inflammasome in human obesity through downregulation of inflammasome gene expression in adipocytes and macrophages. Design Placebo-controlled clinical trial and in vitro coculture experiments with primary human adipocytes (from biopsy specimens) and human THP-1 monocyte-derived macrophages treated with eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA) vs vehicle control. Setting General community, research laboratory. Patients and other participants Obese (body mass index ≥ 30 kg/m2), nondiabetic males and females age 18 to 50. N = 25. Interventions Clinical trial: Eight-week treatment with 4 g Lovaza (EPA and DHA) or placebo. Cells culture: EPA and/or DHA at 100 µg/mL or vehicle control in culture medium. Main outcome measures Adipose tissue or adipocyte/macrophage mRNA expression of IL-1β and IL-18 and circulating IL-18 levels. Results Treatment of obese human subjects with fish oil supplements reduced expression of adipose inflammatory genes including inflammasome-associated IL-18 and IL-1β and circulating IL-18 levels. Both EPA and DHA reduced inflammasome gene expression in obese human adipose and human adipocyte and macrophages. Conclusions N-3 PUFA reduce NLRP3 inflammasome in human adipose through downregulation of gene expression in adipocytes and monocytes/macrophages and has potential as nutritional therapeutic agent in prevention of obesity-related inflammation.

Genetic factors are believed to be primarily responsible for obesity, however, an understanding of how genes for obesity have become so prevalent in modern society has proved elusive. Several theories have attempted to explain the genetic basis for obesity, however none of these appear to factor in the inter-ethnic variation in obesity. Emerging evidence is increasingly pointing to a link between reduced basal metabolism and ineffective brown adipose tissue (BAT) thermogenesis. In fact, brown adipose tissue presence and function is strongly correlated with metabolic rates and directly influences obesity susceptibility. We recently theorized that ancestral exposure to cold necessitated the evolution of enhanced brown adipose tissue thermogenesis, which with today’s hypercaloric and sedentary lifestyle becomes advantageous as thermogenesis is energetically wasteful, raising basal metabolism and burning excess calories. The opposite may be true for the descendants of heat-adapted populations. This review serves to further reconcile global evolutionary climatic exposures with obesity demographics to understand the genetic basis for the obesity pandemic, providing new insights from the most recent studies including those assessing archaic human admixture. Here we outline key genetic variants influencing BAT thermogenesis that have also been linked with climatic exposure to cold and appear to support the theory that evolutionary factors relevant to climate may have shaped the modern obesity pandemic.

Low plasma testosterone (T) levels correlated with metabolic syndrome, cardiovascular diseases, and increased mortality risk. T exerts a significant effect on the regulation of adipose tissue accumulation, and in the glucose and lipids metabolism. Adipocytes are the primary source of the most important adipokines responsible for inflammation and chronic diseases. This review aims to analyze the possible effect of T on the regulation of the proinflammatory cytokines secretion. A systematic literature search on MEDLINE, Google Scholar, and Cochrane using the combination of the following keywords: “testosterone” with “inflammation,” “cytokines,” “adiponectin, CRP, IL-1B, IL-6, TNFα, leptin” was conducted. Sixteen articles related to the effect of low T level and 18 to the effect of T therapy on proinflammatory cytokine were found. T exerts a significant inhibitory effect on adipose tissue formation and the expression of various adipocytokines, such as leptin, TNF-α, IL-6, IL-1, and is positively correlated with adiponectin level, whereas a low T level is correlated with increased expression of markers of inflammation. Further studies are necessary to investigate the role of T, integrated with weight loss and physical activity, on its action on the mechanisms of production and regulation of proinflammatory cytokines.

Context The effects of intensity-specific physical activity (PA) and its interaction with other lifestyle factors on serum adiponectin are currently unclear. Objective To investigate the effects of replacing sedentary time with either light-intensity PA (LPA) or moderate- to vigorous-intensity PA (MVPA) on total and high-molecular-weight (HMW) adiponectin and to examine interactions with smoking, alcohol drinking, coffee consumption, and menopausal status in a general population. Design/setting Cross-sectional study of 4013 men and 6050 women (40 to 69 years of age). Main outcome measures The associations of replacing sedentary time with LPA or MVPA on total and HMW adiponectin were analyzed using an isotemporal substitution model. Results In men, reallocating 60 minutes of sedentary time to 60 minutes of LPA was associated with 9% and 13% higher total and HMW adiponectin levels even after adjusting for confounders, although such associations were not observed for MVPA. A similar pattern of results was also seen in women. The effect of replacing sedentary time with LPA on adiponectin was clearer in middle/high coffee consumers than in low coffee consumers among women. Although increasing the effect of replacing sedentary time with MVPA on adiponectin was clearer in former/current smokers than in never smokers among men, the replacement effect for MVPA on total adiponectin was clearer in premenopausal women than in postmenopausal women. Conclusions Replacing sedentary time with LPA resulted in increased levels of total and HMW adiponectin. The replacement effects for LPA or MVPA were found to be multiply modified by smoking, coffee consumption, and menopausal status.

Several case series of extreme early-onset obesity due to mutations in the human leptin receptor (LEPR) gene have been reported. In this review we summarize published functional and phenotypic data on mutations in the human LEPR gene causing severe early-onset obesity. Additionally, we included data on six new cases from our obesity center. Literature research was performed using PubMed and OMIM. Functional relevance of mutations was estimated based on reported functional analysis, mutation size, and location, as well as phenotypic characteristics of affected patients. We identified 57 cases with 38 distinct LEPR mutations. We found severe early-onset obesity, hyperphagia, and hypogonadotropic hypogonadism as cardinal features of a complete loss of LEPR function. Other features, for example, metabolic disorders and recurring infections, were variable in manifestation. Obesity degree or other manifestations did not aggregate by genotype. Few patients underwent bariatric surgery with variable success. Most mutations occurred in the fibronectin III and cytokine receptor homology II domains, whereas none was found in cytoplasmic domain. In silico data were available for 25 mutations and in vitro data were available for four mutations, revealing residual activity in one case. By assessing provided information on the clinical phenotype, functional analysis, and character of the 38 mutations, we assume residual LEPR activity for five additional mutations. Functional in vitro analysis is necessary to confirm this assumption.

Objective Fatty liver disease is increased among individuals with HIV. We sought to explore how aldosterone, a key hormone linked to insulin resistance and inflammation, relates to liver fat in the large population of individuals with HIV and metabolic abnormalities. Methods Forty-six individuals with HIV and increased waist circumference and dysglycemia were assessed for liver fat using proton magnetic resonance spectroscopy. Serum aldosterone level was obtained following strictly controlled posture conditions and a standardized sodium diet and was related to liver fat. Results Among the entire group [median (interquartile range) liver fat: 5% (3%, 12%) and homeostatic model assessment of insulin resistance: 1.74 (1.21, 2.83)], serum aldosterone significantly correlated with liver fat (r = 0.31; P = 0.049). Liver fat level was significantly higher in those with aldosterone above vs below the median [8% (3%, 20%) vs 4% (2%, 10%); P = 0.02]. In the presence of metabolic syndrome, individuals with aldosterone levels above vs below the median had markedly elevated liver fat values [14% (9%, 23%) vs 5% (3%, 12%); P = 0.005] and increased presence of fatty liver disease (FLD; 92% vs 50%; P = 0.02). Controlling for metabolic syndrome, hepatitis C virus, and alcohol use, aldosterone was a significant and independent predictor of liver fat (β estimate: 0.6038, P = 0.01; overall model r2 = 0.41, P = 0.0005) and FLD (OR: 1.38, P = 0.02; overall model r2 = 0.28, P = 0.002). Conclusion These data highlight a robust association between aldosterone and liver fat among individuals with HIV and metabolic dysregulation. Increased aldosterone may be a risk factor for liver fat accumulation among the population with HIV.

Context Monogenic partial lipodystrophy is a genetically heterogeneous disease where only variants with specific genetic mechanisms are causative. Three heterozygous protein extending frameshift variants in PLIN1 have been reported to cause a phenotype of partial lipodystrophy and insulin resistance. Objective We investigated if null variants in PLIN1 cause lipodystrophy. Methods As part of a targeted sequencing panel test, we sequenced PLIN1 in 2208 individuals. We also investigated the frequency of PLIN1 variants in the gnomAD database, and the type 2 diabetes knowledge portal. Results We identified 6/2208 (1 in 368) individuals with a PLIN1 null variant. None of these individuals had clinical or biochemical evidence of overt lipodystrophy. Additionally, 14/17,000 (1 in 1214) individuals with PLIN1 null variants in the type 2 diabetes knowledge portal showed no association with biomarkers of lipodystrophy. PLIN1 null variants occur too frequently in gnomAD (126/138,632; 1 in 1100) to be a cause of rare overt monogenic partial lipodystrophy. Conclusions Our study suggests that heterozygous variants that are predicted to result in PLIN1 haploinsufficiency are not a cause of familial partial lipodystrophy and should not be reported as disease-causing variants by diagnostic genetic testing laboratories. This finding is in keeping with other known monogenic causes of lipodystrophy, such as PPARG and LMNA, where only variants with specific genetic mechanisms cause lipodystrophy., PLIN1 frameshift variants were reported to cause lipodystrophy. We investigated sequencing data from over 140,000 people and established that null variants in PLIN1 do not cause lipodystrophy.

Context The hypothalamic melanocortin 4 receptor (MC4R) pathway serves a critical role in regulating body weight. Loss of function (LoF) mutations in the MC4R pathway, including mutations in the pro-opiomelanocortin (POMC), prohormone convertase 1 (PCSK1), leptin receptor (LEPR), orMC4R genes, have been shown to cause early-onset severe obesity. Methods Through a comprehensive epidemiological analysis of known and predicted LoF variants in thePOMC, PCSK1, andLEPR genes, we sought to estimate the number of US individuals with biallelic MC4R pathway LoF variants. Results We predict ~650α-melanocyte-stimulating hormone (MSH)/POMC, 8500PCSK1, and 3600LEPR homozygous and compound heterozygous individuals in the United States, cumulatively enumerating >12,800 MC4R pathway–deficient obese patients. Few of these variants have been genetically diagnosed to date. These estimates increase when we include a small subset of less rare variants:β-MSH/POMC,PCSK1 N221D, and aPCSK1 LoF variant (T640A). To further define the MC4R pathway and its potential impact on obesity, we tested associations between body mass index (BMI) and LoF mutation burden in thePOMC, PCSK1, andLEPR genes in various populations. We show that the cumulative allele burden in individuals with two or more LoF alleles in one or more genes in the MC4R pathway are predisposed to a higher BMI than noncarriers or heterozygous LoF carriers with a defect in only one gene. Conclusions Our analysis represents a genetically rationalized study of the hypothalamic MC4R pathway aimed at genetic patient stratification to determine which obese subpopulations should be studied to elucidate MC4R agonist (e.g., setmelanotide) treatment responsiveness., This is a genetic epidemiology study of melanocortin 4 receptor (MC4R) pathway dysfunction in obesity aimed at genetic patient stratification for clinical study of MC4R agonist treatment responsiveness.

Neuropeptide Y (NPY)/Agouti-related protein (AgRP) neurons in the arcuate nucleus of the hypothalamus are part of a neuroendocrine feedback loop that regulates feeding behavior and glucose homeostasis. NPY/AgRP neurons sense peripheral signals (including the hormones leptin, insulin, and ghrelin) and integrate those signals with inputs from other brain regions. These inputs modify both long-term changes in gene transcription and acute changes in the electrical activity of these neurons, leading to a coordinated response to maintain energy and glucose homeostasis. However, the mechanisms by which the hormones insulin and leptin acutely modify the electrical activity of these neurons remain unclear. In this study, we show that loss of the phosphoinositide 3-kinase catalytic subunits p110α and p110β in AgRP neurons abrogates the leptin- and insulin-induced inhibition of AgRP neurons. Moreover, continual disruption of p110α and p110β in AgRP neurons results in increased weight gain. The increased adiposity was concomitant with a hypometabolic phenotype: decreased energy expenditure independent of changes in food intake. Deficiency of p110α and p110β in AgRP neurons also impaired glucose homeostasis and insulin sensitivity. In summary, these data highlight the requirement of both p110α and p110β in AgRP neurons for the proper regulation of energy balance and glucose homeostasis., Deficiency of both p110α and p110β in AgRP neurons abrogates acute inhibition of leptin and insulin as well as proper energy balance and glucose homeostasis.

Context Growth hormone deficiency (GHD) leads to obesity and may induce tissue hypoxia. As (pro)renin receptor [(P)RR] is reported to contribute to the aerobic metabolism by stabilizing pyruvate dehydrogenase (PDH), it may play a substantial role in GHD. Objective We aimed to investigate serum soluble (P)RR [s(P)RR] concentration, the origin of s(P)RR, and significance of (P)RR in GHD. Design, Setting, and Participants Serum s(P)RR concentration was examined in 72 patients with pituitary diseases, including 32 patients with severe GHD (SGHD) and after GH replacement in 16 SGHD patients. Leptin-deficient ob/ob obese mice were treated with pegvisomant, a GH receptor antagonist, to explore the source of elevated serum s(P)RR in GHD. Adipocytes were cultured with 5% O2 to examine the effects of hypoxia. Results Serum s(P)RR concentration was higher in patients with SGHD than in those without SGHD. Obesity was the important determinant of s(P)RR concentration. Serum s(P)RR concentration significantly decreased after GH replacement in SGHD patients. (P)RR mRNA expression was increased specifically in the adipose tissue (AT) of pegvisomant-treated obese mice compared with that of control obese mice. Hypoxia in cultured adipocytes increased (P)RR expression without affecting the PDH E1 β subunit (PDHB) expression; however, with (P)RR knockdown by small interfering RNA, hypoxia significantly decreased the expression of PDHB. Conclusion GHD patients showed increased serum s(P)RR concentration, possibly caused by obesity and hypoxia. (P)RR expression in AT of GHD patients may be elevated to help maintain aerobic metabolism under hypoxia. Thus, the elevated serum s(P)RR level may reflect hypoxia in ATs., Serum (pro)renin receptor [(P)RR] concentrations were elevated in GHD patients and mice, which may reflect adipocyte hypoxia-induced (P)RR interacting with PHDB to maintain aerobic metabolism.

Context: Plasma adiponectin concentration has been shown to be inversely associated with body mass index (BMI) and insulin resistance in cross-sectional research. However, it is unclear whether adiponectin predicts future body composition and insulin resistance. Objective: We aimed to investigate the potential relationship between adiponectin concentration and future regional body fat distribution and insulin resistance. Design and Setting: This was a community-based prospective cohort study with 5 years of follow-up. Participants: A total of 218 Japanese Americans without diabetes (79 men, 139 women, mean age 51.7 ± 10.1 years) were assessed at baseline and after 5 years of follow-up. Main Outcome Measures: Abdominal visceral and subcutaneous fat area and thigh subcutaneous fat area were measured by computed tomography (CT). Insulin resistance was evaluated by homeostasis model assessment 2 of insulin resistance (HOMA2-IR). Plasma total adiponectin was measured by radioimmunoassay. Results: Baseline adiponectin was inversely associated with abdominal visceral fat area (P = 0.037) and HOMA2-IR (P = 0.002) at 5 years in a multiple linear regression model after adjustment for baseline traits (including age, sex, BMI, abdominal visceral fat area, abdominal subcutaneous fat area, thigh subcutaneous fat area, HOMA2-IR) and weight change. However, no association was seen between baseline adiponectin concentration and BMI or other CT-measured regional fat depots at 5 years. Conclusions: Low plasma adiponectin concentration independently predicted future abdominal visceral fat accumulation and increased insulin resistance in Japanese Americans., We studied the relationship between baseline adiponectin and future body composition and insulin resistance. Low plasma adiponectin predicted visceral fat accumulation and greater insulin resistance.

The paraventricular nucleus (PVN) is a critical locus of energy balance control. Three sets of neurons in the PVN are involved in regulating energy balance: oxytocin-expressing neurons (OXT-neurons), thyrotropin-releasing hormone–expressing neurons, and corticotrophin-releasing hormone–expressing neurons. To examine the role of OXT-neurons in energy balance, we ablated these neurons in mice by injecting diphtheria toxin into mice possessing both the oxytocin promoter driving cre expression and a cre-inducible diphtheria toxin receptor. Immunohistochemistry and real-time reverse transcriptase polymerase chain reaction confirmed that this injection caused a significant decrease in PVN OXT-neurons and OXT-mRNA abundance. OXT-neuron ablation did not alter food intake, weight, or energy expenditure at room temperature on either chow or a high-fat diet. To further characterize OXT-neuron–ablated mice, we examined their response to 1) intraperitoneal cholecystokinin (CCK) injection and 2) thermogenic stress. OXT-neuron–ablated mice had a blunted decrease in feeding response to CCK. When exposed to the extreme cold (4°C) for 3 hours, OXT-neuron–ablated mice had significant decreases in both rectal and brown adipose tissue temperature relative to controls, which was rescued by OXT treatment. Thermographic imaging revealed that OXT-neuron–ablated mice had increased body surface temperature. Thus, we report that OXT-neuron ablation shows no role for OXT-neurons in energy homeostasis at neutral temperature but reveals a heretofore unappreciated role for OXT-neurons and oxytocin specifically in regulating the thermogenic stress response., At 4°C, OXT-neuron–ablated mice had decreased core and BAT temperature rescued by oxytocin. OXT-neuron ablation reveals a role for oxytocin in thermogenic stress response control.

Context: Familial partial lipodystrophy type 1 (FPLD1) is an extreme form of central adiposity, with peripheral lipodystrophy associated with severe manifestations of the metabolic syndrome, often poorly responsive to standard therapeutic approaches. Body mass index in FPLD1 varies but, in many cases, is below the level at which metabolic surgery is usually considered as a therapeutic option. Design: We detailed the metabolic response to gastric bypass surgery of three patients with FPLD1, refractory to medical therapy. Results: Roux-en-Y gastric bypass (RYGB) was associated with weight loss and substantial improvements in glycemic control and insulin sensitivity. All three patients were able to stop using insulin. Glucose tolerance testing in one patient demonstrated an increase in L-cell–derived gut hormone responses postoperatively. Conclusion: RYGB surgery substantially improved glycemic control in three patients with FPLD1, two of whom had body mass indices below 30 kg/m2. RYGB should be considered in patients with partial lipodystrophy and refractory metabolic disease., We studied the clinical response of three patients with familial partial lipodystrophy type 1 and refractory diabetes to RYGB surgery and documented dramatic clinical improvements.

Purpose: Previous studies have shown that microvascular dysfunction (MD) is associated with a number of cardiovascular risk factors, including obesity. Few studies have assessed microvascular reactivity in children, and in most of these, results were confounded by the effects of puberty. Our aim was to establish whether MD is already present in obese prepubertal children. Methods: This cross-sectional study included 52 obese, 18 overweight, and 28 eutrophic children, with a mean ± standard deviation age of 7.44 ± 1.22 years. We evaluated cardiovascular risk factors and nutritive microvascular function by using nailfold dynamic videocapillaroscopy and determined functional capillary density (FCD), red blood cell velocity at resting conditions (RBCV) and at peak (RBCVmax), and time to reach peak velocity during the post-occlusive reactive hyperemic response following 1 minute ischemia. Results: On univariate analysis, differences in microvascular reactivity were not observed among the groups. Obese and overweight children had significantly higher scores than eutrophic children for the following parameters: body mass index, waist circumference, waist-to-height ratio, mean arterial pressure, homeostasis model assessment for insulin resistance, levels of insulin, leptin, glucose, triglycerides, total cholesterol, uric acid, and C-reactive protein. Multivariate analysis demonstrated the association between metabolic, anthropometric, and microvascular variables, stratified according to the degree of adiposity and body fat distribution. Conclusions: Univariate analysis did not show any difference in microvascular reactivity between groups but, by testing these variables by multivariate means, we noticed a common and direct variation between cardiovascular/metabolic risk factors and microvascular reactivity occurring early in life., This study shows that prepubertal children do not have microvascular dysfunction; however, some of the surrogate cardiovascular risk markers are already associated with microvascular reactivity.

Context: Obesity is associated with subclinical white adipose tissue inflammation, as defined by the presence of crown-like structures (CLSs) consisting of dead or dying adipocytes encircled by macrophages. In humans, bariatric surgery-induced weight loss leads to a decrease in CLSs, but the effects of rapid diet-induced weight loss on CLSs and metabolism are unclear. Objective: To determine the effects of rapid very-low-calorie diet-induced weight loss on CLS density, systemic biomarkers of inflammation, and metabolism in obese postmenopausal women. Design: Prospective cohort study. Setting: Rockefeller University Hospital, New York, NY. Participants: Ten obese, postmenopausal women with a mean age of 60.6 years (standard deviation, ±3.6 years). Main Outcome Measures: Effects on CLS density and gene expression in abdominal subcutaneous adipose tissue, cardiometabolic risk factors, white blood count, circulating metabolites, and oxidative stress (urinary isoprostane-M) were measured. Results: Obese subjects lost approximately 10% body weight over a mean of 46 days. CLS density increased in subcutaneous adipose tissue without an associated increase in proinflammatory gene expression. Weight loss was accompanied by decreased fasting blood levels of high-sensitivity C-reactive protein, glucose, lactate, and kynurenine, and increased circulating levels of free fatty acids, glycerol, β-hydroxybutyrate, and 25 hydroxyvitamin D. Levels of urinary isoprostane-M declined. Conclusion: Rapid weight loss stimulated lipolysis and an increase in CLS density in subcutaneous adipose tissue in association with changes in levels of circulating metabolites, and improved systemic biomarkers of inflammation and insulin resistance. The observed change in levels of metabolites (i.e., lactate, β-hydroxybutyrate, 25 hydroxyvitamin D) may contribute to the anti-inflammatory effect of rapid weight loss., Rapid diet-induced weight loss increases subcutaneous adipose crown-like structure density in obese postmenopausal women.

Context: Severe obesity is one of the major features of Bardet-Biedl syndrome (BBS) and causes reduced life expectancy. Bariatric surgery is an effective treatment of morbid obesity. Data on the effect of bariatric surgery for monogenic obesity is essentially lacking. We present the clinical and metabolic 3-year follow-up of sleeve gastrectomy in a BBS patient. Case Description: A 37-year-old obese woman with BBS (body mass index, 40 kg/m2) was referred to our clinic for uncontrolled diabetes, dyslipidemia, hypertension, and nonalcoholic fatty liver disease (NAFLD). After sleeve gastrectomy, progressive weight loss was observed, with a 32% total weight loss at 3-year follow-up. Glycemic control and NAFLD improved significantly. Blood pressure normalized, and treatment was discontinued 3 months after surgery. Conclusions: Laparoscopic sleeve gastrectomy can be a safe and effective treatment of morbid BBS-related obesity in adult patients. Significant and sustained weight loss leads to the improvement of several obesity-related comorbidities such as diabetes, hypertension, and NAFLD, as in polygenic obesity. Further data are needed to confirm the long-term efficacy and safety of bariatric surgery in BBS., We present the 3-year follow-up after sleeve gastrectomy in a BBS patient. Significant weight loss improved several obesity-related comorbidities. No major complication was observed.

The protein kinase A (PKA) signaling system mediates the effects of numerous hormones, neurotransmitters, and other molecules to regulate metabolism, cardiac function, and more. PKA defects may lead to diverse phenotypes that largely depend on the unique expression profile of the affected subunit. Deletion of the Prkarcb gene, which codes for PKA catalytic subunit β (Cβ), protects against diet-induced obesity (DIO), yet the mechanism for this phenotype remains unclear. We hypothesized that metabolic rate would be increased in Cβ knockout (KO) mice, which could explain DIO resistance. Male, but not female, CβKO mice had increased energy expenditure, and female but not male CβKO mice had increased subcutaneous temperature and increased locomotor activity compared with wild-type (WT) littermates. Urinary norepinephrine (NE) and normetanephrine were elevated in female CβKO mice. CβKO mice had increased heart rate (HR); blocking central NE release normalized HR to that of untreated WT mice. Basal and stimulated PKA enzymatic activities were unchanged in adipose tissue and heart and varied in different brain regions, suggesting that Prkacb deletion may mediate signaling changes in specific brain nuclei and may be less important in the peripheral regulation of PKA expression and activity. This is a demonstration of a distinct effect of the PKA Cβ catalytic subunit on catecholamines and sympathetic nerve signaling. The data provide an unexpected explanation for the metabolic phenotype of CβKO mice. Finally, the sexual dimorphism is consistent with mouse models of other PKA subunits and adds to the importance of these findings regarding the PKA system in human metabolism.

Context Spexin is a newly identified neuropeptide that is involved in satiety control, glucose, and lipids metabolism. It has also been related to human diseases, such as obesity and type 2 diabetes. However, whether spexin changes with age or not is still unclear. Objective The aim of this study is to investigate the relationship between circulating spexin levels and age and to study their interaction effects on body mass index (BMI), fasting glucose, and -lipids. Design and Participants This is a cross-sectional study, including 68 healthy adult women whose ages are in a wide range (minimum: 23; median: 38.5; maximum: 64). Outcome Measures The serum spexin levels were measured by an enzyme-linked immunosorbent assay. Fasting glucose, total cholesterol, triglycerides (TG), alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, urea, and creatinine were measured by routine biochemical test. Shapiro-Wilk’s test, Spearman and Pearson correlation analyses, χ2 test, and two-way analysis of variance were used to interpret the data. Results Serum spexin levels are significantly correlated with age (Spearman r = −0.277, P = 0.022), BMI (Spearman r = −0.445, P < 0.001), fasting glucose (Spearman r = −0.302, P = 0.014), and TG (Spearman r = −0.324, P = 0.008). Spexin levels independently predict the risk of high BMI and high fasting glucose. No interaction effects of spexin and age on BMI and fasting glucose were found. Conclusions Circulating spexin levels decrease with age, suggesting a possible role of this peptide in aging-related functions and disorders. Further investigations are needed to expand the clinical significance of this finding., Circulating spexin levels negatively correlate with age and independently predict risk of high body mass index and fasting glucose in healthy adult women.

Context and Objectives: Spillover of fatty acids (FAs) into the plasma nonesterified fatty acid (NEFA) pool, because of an inability of adipose tissue (AT) to accommodate sufficient fat uptake, has been suggested to contribute to obesity-related insulin resistance. Using specific labeling techniques, we compared the proportion of spillover-derived NEFA across a range of adiposity. Participants and Methods: Seventy-one healthy men and women were fed a mixed meal (40 g fat) containing [U13C]palmitate to assess the contribution of chylomicron-derived spillover FAs. To investigate subcutaneous abdominal-specific spillover, arteriovenous difference and stable-isotope methodologies were used in substudy (six men, six women). Results: Chylomicron-derived FA spillover was higher in individuals with a BMI, The proportion of diet-derived spillover fatty acids was assessed in healthy adults. There was a more dynamic and greater degree of postprandial spillover of fatty acids in lean individuals and women.

Context: The experimental paradigm of acute caloric restriction (CR) followed by refeeding (RF) can be used to study the homeostatic mechanisms that regulate energy homeostasis, which are relevant to understanding the adaptive response to weight loss. Objective: Metabolomics, the measurement of hundreds of small molecule metabolites, their precursors, derivatives, and degradation products, has emerged as a useful tool for the study of physiology and disease and was used here to study the metabolic response to acute CR. Participants, Design, and Setting: We used four ultra high-performance liquid chromatography-tandem mass spectrometry methods to characterize changes in carbohydrates, lipids, amino acids, and steroids in eight normal weight men at baseline, after 48 hours of CR (10% of energy requirements) and after 48 hours of ad libitum RF in a tightly controlled environment. Results: We identified a distinct metabolomic signature associated with acute CR characterized by the expected switch from carbohydrate to fat utilization with increased lipolysis and β-fatty acid oxidation. We found an increase in ω-fatty acid oxidation and levels of endocannabinoids, which are known to promote food intake. These changes were reversed with RF. Several plasmalogen phosphatidylethanolamines (endogenous antioxidants) significantly decreased with CR (all P ≤ 0.0007). Additionally, acute CR was associated with an increase in the branched chain amino acids (all P ≤ 1.4 × 10−7) and dehydroepiandrosterone sulfate (P = 0.0006). Conclusions: We identified a distinct metabolomic signature associated with acute CR. Further studies are needed to characterize the mechanisms that mediate these changes and their potential contribution to the adaptive response to dietary restriction., We conducted a metabolomic analysis of 770 small molecules in eight healthy lean men and identified a distinct metabolomic signature associated with acute caloric restriction.

Context: A diminished muscle anabolic response to protein nutrition may underpin age-associated muscle loss. Objective: To determine how chronological and biological aging influence myofibrillar protein synthesis (MyoPS). Design: Cross-sectional comparison. Setting: Clinical research facility. Participants: Ten older lean [OL: 71.7 ± 6 years; body mass index (BMI) ≤25 kg ⋅ m−2], 7 older obese (OO: 69.1 ± 2 years; BMI ≥30 kg ⋅ m−2), and 18 young lean (YL) individuals (25.5 ± 4 years; BMI ≤25 kg ⋅ m−2). Intervention: Skeletal muscle biopsies obtained during a primed-continuous infusion of l-[ring-13C6]-phenylalanine. Main Outcome Measures: Anthropometrics, insulin resistance, inflammatory markers, habitual diet, physical activity, MyoPS rates, and fiber-type characteristics. Results: Fat mass, insulin resistance, inflammation, and type II fiber intramyocellular lipid were greater, and daily step count lower, in OO compared with YL and OL. Postprandial MyoPS rates rose above postabsorptive values by ∼81% in YL (P < 0.001), ∼38% in OL (P = 0.002, not different from YL), and ∼9% in OO (P = 0.11). Delta change in postprandial MyoPS from postabsorptive values was greater in YL compared with OL (P = 0.032) and OO (P < 0.001). Absolute postprandial MyoPS rates and delta postprandial MyoPS change were associated with step count (r2 = 0.33; P = 0.015) and leg fat mass (r2 = 0.4; P = 0.006), respectively, in older individuals. Paradoxically, lean mass was similar between groups, and muscle fiber area was greater in OO vs OL (P = 0.002). Conclusion: Age-related muscle anabolic resistance is exacerbated in obese inactive individuals, with no apparent detriment to muscle mass., We studied how chronological and biological aging influence muscle anabolism and found that nutrient-stimulated muscle protein synthesis rates are impaired in obese, inactive older individuals.

Podocan, a member of the small leucine-rich repeat proteoglycans (SLRPs), is expressed in vascular endothelial cells with high levels of expression in the sclerotic glomerular lesions of experimental HIV-associated nephropathy. It is also found in vascular smooth muscle cells and is involved in atherosclerosis. Decorin, a protein similar to podocan, also belongs to the SLRP family and is highly expressed in adipose tissues. It is a secreted protein associated with obesity, type 2 diabetes, and diabetic nephropathy. Based on the similarity of podocan to decorin and its functions reported in the renal and cardiovascular systems, we hypothesized that podocan levels might correlate with the occurrence of metabolic syndromes such as obesity, diabetes, and diabetic nephropathy. We found that podocan was highly expressed in the adipose tissue of mice and humans and its expression was regulated by tumor necrosis factor-α in mouse 3T3-L1 adipocytes. In addition, podocan was detected in the plasma, and its levels tended to increase in diet-induced obese C57BL/6J mice and decrease in obese-diabetic KKAy and db/db mice. Podocan messenger RNA (mRNA) levels in the renal cortex correlated negatively with the urinary albumin-to-creatinine ratio, a surrogate marker of glomerular injury in uninephrectomized db/db mice used as a model of diabetic nephropathy. Our results suggest that podocan is involved in kidney function and could be a unique therapeutic target for diabetic nephropathy., We investigated podocan, which was highly expressed in adipose tissue, present in plasma, and associated with diabetic nephropathy in mice.

ESSENTIAL POINTS The daily rhythmicity of plasma glucocorticoid (GC) levels is a strong modulator of many physiological and psychological processes, although its functional significance is poorly understood. The suprachiasmic nuclei of the hypothalamus have been shown to harbor a molecular clock mechanism generating circadian rhythmicity in mammals, but the same mechanism is present in many peripheral tissues and elsewhere in the brain. Mineralocorticoid receptors and glucocorticoid receptors mediate the action of naturally occurring GC in complementary fashion. Optimal physiological effects of GC occur when the central signal that controls the rhythm of GC release and the peripheral rhythms in tissues expressing GC receptors are aligned. New studies suggest that misalignment of central and peripheral oscillators may increase the risk of disease, with adverse effects on the immune system, cardiovascular system and metabolism, among others prominent. Chronopharmacological strategies that attempt to normalize the rhythm of circulating GCs have potential to improve the treatment of a wide variety of physical and mental conditions., Adrenal glucocorticoids are major modulators of multiple functions, including energy metabolism, stress responses, immunity, and cognition. The endogenous secretion of glucocorticoids is normally characterized by a prominent and robust circadian (around 24 hours) oscillation, with a daily peak around the time of the habitual sleep-wake transition and minimal levels in the evening and early part of the night. It has long been recognized that this 24-hour rhythm partly reflects the activity of a master circadian pacemaker located in the suprachiasmatic nucleus of the hypothalamus. In the past decade, secondary circadian clocks based on the same molecular machinery as the central master pacemaker were found in other brain areas as well as in most peripheral tissues, including the adrenal glands. Evidence is rapidly accumulating to indicate that misalignment between central and peripheral clocks has a host of adverse effects. The robust rhythm in circulating glucocorticoid levels has been recognized as a major internal synchronizer of the circadian system. The present review examines the scientific foundation of these novel advances and their implications for health and disease prevention and treatment.

Context: Glucocorticoids have pleiotropic metabolic functions, and acute glucocorticoid excess affects fatty acid metabolism, increasing systemic lipolysis. Whether glucocorticoids exert adipose tissue depot-specific effects remains unclear. Objective: To provide an in vivo assessment of femoral and abdominal adipose tissue responses to acute glucocorticoid administration. Design and Outcome Measures: Nine healthy male volunteers were studied on two occasions, after a hydrocortisone infusion (0.2 mg/kg/min for 14 hours) and a saline infusion, respectively, given in randomized double-blind order. The subjects were studied in the fasting state and after a 75-g glucose drink with an in vivo assessment of femoral adipose tissue blood flow (ATBF) using radioactive xenon washout and of lipolysis and glucose uptake using the arteriovenous difference technique. In a separate study (same infusion design), eight additional healthy male subjects underwent assessment of fasting abdominal ATBF and lipolysis only. Lipolysis was assessed as the net release of nonesterified fatty acids (NEFAs) from femoral and abdominal subcutaneous adipose tissue. Results: Acute hypercortisolemia significantly increased basal and postprandial ATBF in femoral adipose tissue, but the femoral net NEFA release did not change. In abdominal adipose tissue, hypercortisolemia induced substantial increases in basal ATBF and NEFA release. Conclusions: Acute hypercortisolemia induces differential lipolysis and ATBF responses in abdominal and femoral adipose tissue, suggesting depot-specific glucocorticoid effects. Abdominal, but not femoral, adipose tissue contributes to the hypercortisolemia-induced systemic NEFA increase, with likely contributions from other adipose tissue sources and intravascular triglyceride hydrolysis., Acute experimental hypercortisolemia induces differential metabolic responses in abdominal and femoral adipose tissue in vivo, suggesting depot-specific glucocorticoid effects in humans.

Context: Body fat and body composition distribution patterns affect diabetes risk and glycemic control, but most studies use proxy measures (e.g., body mass index). Objective: This study examined the association of percent body fat and lean mass with glycated hemoglobin (HbA1c) in US adults. Design: The National Health and Nutrition Examination Survey (NHANES) is a program of cross-sectional studies that enroll nationally representative samples of the US civilian noninstitutionalized population. Setting: NHANES is designed to assess the health status of adults and children throughout the United States. Participants: This study included 11,125 participants aged 18 to 69 years from the 1999 through 2006 NHANES, comprising 846 persons with diagnosed diabetes and 10,125 without diabetes. Main Outcome Measures: Total and abdominal (trunk) percent body fat and lean mass were measured using dual-energy x-ray absorptiometry. Linear and logistic regression analyses were used to examine their association with HbA1c. Results: Among those without diagnosed diabetes, total and trunk percent body fat, as well as trunk and total lean mass, were strongly associated with elevated HbA1c; odds ratios per 5% increment for the association of percent body fat with HbA1c >5.7% (39 mmol/mol) ranged from 1.60 to 2.01 across age and sex categories. Among adults with diabetes, higher total percent fat was associated with higher HbA1c in males age, This study examines the independent association of percent body fat and lean mass with HbA1c in a nationally representative sample of US adults.

Context: Wnt1-inducible signaling pathway protein 1 (WISP1) is a novel adipokine participating in adipose tissue (AT) dysfunction; so far, no data on WISP1 in diabetes are available. Objectives: To evaluate plasma WISP1 in subjects with type 2 diabetes (T2D) and its correlates linked to AT inflammation. Design and Participants: For this cross-sectional study, 97 consecutive dysmetabolic patients were recruited at the diabetes outpatient clinics of Sapienza University in Rome; 71 of them had T2D, with (n = 35) or without (n = 36) obesity, and 26 were obese patients without diabetes. Twenty-one normal-weight nondiabetic individuals were enrolled as a control group. Study participants underwent clinical workup and blood sampling for metabolic/inflammatory characterization; magnetic resonance imaging (MRI) data on subcutaneous AT and visceral AT (VAT) area, hepatic fat content, and VAT homogeneity were available for most diabetic patients. Results: Plasma WISP1 significantly increased throughout classes of obesity and correlated with greater VAT area, interleukin-8 (IL-8), and lower adiponectin levels, without differing between diabetic and nondiabetic participants. Higher IL-8 was the main determinant of increased WISP1. MRI-assessed VAT inhomogeneity was associated with higher WISP1, IL-8 and C-reactive protein levels, independent of obesity; high WISP1 strongly predicted VAT inhomogeneity (P < 0.001). Conclusions: WISP1 levels are increased in obese persons and are directly related to adiposity, independent of glycemic status or insulin resistance; moreover, they are strongly associated with increased plasma IL-8 and signal abnormalities of VAT. The overall data add insights to the mechanisms underlying metabolic alterations and may open a scenario for innovative therapeutic approaches for diabetes prevention and care., This study of plasma Wnt1-inducible signaling pathway protein 1 (WISP1) in dysmetabolic patients and controls found that higher WISP1 levels strongly correlated with obesity and adipose tissue dysfunction, independent of diabetes.

Context: The role of the extracellular matrix (ECM) in regulating adipocyte metabolism in the context of metabolic disease is poorly defined. Objective: The objective of this study was to define the metabolic phenotype of adipocytes associated with human diabetes (DM) and the role of the ECM in regulating adipocyte metabolism. Design: Adipose tissues from obese patients were studied in standard 2-dimensional (2D) cell culture and an in vitro model of decellularized adipose tissue ECM repopulated with human adipocytes, and results were correlated with DM status. Setting: This study was conducted at the Academic University Medical Center and Veteran’s Administration Hospital. Patients: Seventy patients with morbid obesity undergoing bariatric surgery were included in the study. Interventions: Visceral and subcutaneous adipose tissues were collected at the time of bariatric surgery. Outcome measures: This study used metabolic assays for glucose uptake, lipolysis, and lipogenesis in adipocytes in 2D cell culture and 3-dimensional ECM culture. Results: Adipocytes from subjects with DM manifest decreased glucose uptake and decreased lipolysis in 2D culture. ECM supports differentiation of mature adipocytes and recapitulates DM-specific differences in adipocyte metabolism observed in 2D culture. ECM from subjects without DM partially rescues glucose uptake and lipolytic defects in adipocytes from subjects with DM, whereas ECM from subjects with DM impairs glucose uptake in adipocytes from subjects without DM. Conclusions: DM is associated with adipocyte metabolic dysfunction. The ECM regulates adipocyte metabolism. Nondiabetic ECM rescues metabolic dysfunction in DM adipocytes, whereas DM ECM imparts features of metabolic dysfunction to nondiabetic adipocytes. These findings suggest the ECM as a target for manipulating adipose tissue metabolism., An in vitro model of adipose tissue extracellular matrix repopulated with adipocytes was used to demonstrate that the extracellular matrix regulates adipocyte metabolism in a disease-specific manner.

Context: Exposure to maternal adiposity during pregnancy is associated with higher offspring birth weight and greater adiposity through childhood and adult life. As birth weight reflects the summation of lean and fat mass, the extent to which fat mass at birth tracks into later life is unknown. Objective: To determine whether fat mass at birth is associated with child and adolescent adiposity. Design, Setting, and Participants: UK birth cohort with markers of neonatal fat mass; cord blood leptin, adiponectin, and birth weight and adiposity outcomes at age 9 (n = 2775) and 17 years (n = 2138). Main Outcomes: Offspring body mass index (BMI), waist circumference, dual-energy X-ray absorptiometry–determined fat mass, and obesity at age 9 and 17 years. Results: Higher cord blood leptin was associated with higher z scores of fat mass [difference in mean per 10 pg/mL: 0.03 standard deviation (SD); 95% confidence interval (CI), 0.00 to 0.06], waist circumference (0.04 SD; 95% CI, 0.00 to 0.07), and BMI (0.04 SD; 95% CI, 0.00 to 0.08) at age 9. However, by age 17 the adjusted results were attenuated to the null. Cord blood adiponectin was not associated with measures of adiposity at age 9. At age 17, cord blood adiponectin was positively associated with fat mass (0.02 SD per 10 μg/mL; 95% CI, 0.02 to 0.03) and waist circumference (0.04 SD per 10 μg/mL; 95% CI, 0.03 to 0.05). Birth weight was positively associated with waist circumference (0.03 SD per 100 g; 95% CI, 0.02 to 0.04) and BMI (0.02 SD per 100 g; 95% CI, 0.00 to 0.03), but not fat mass or odds of obesity. Cord blood leptin and adiponectin were not associated with obesity at either age. Conclusions: Increased cord blood leptin and adiponectin, known surrogates of fetal fat mass, were weakly associated with increased fat mass in late childhood and adolescence, respectively., We found that cord blood leptin and adiponectin, known surrogates of fetal fat mass, were weakly positively associated with some measures of fat mass in late childhood and adolescence.