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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.

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.

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.

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.

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.

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 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.

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.

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.

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.

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: 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.