Adipose Function Research Articles

Sitagliptin Decreases Visceral Fat and Blood Glucose in Women With Polycystic Ovarian Syndrome.

Women with polycystic ovarian syndrome (PCOS) have decreased growth hormone (GH), which can result in increased visceral adiposity (VAT) and impaired vascular function. GH-releasing hormone, a dipeptidyl peptidase-4 (DPP4) substrate, stimulates GH secretion. We tested the hypothesis that DPP4 inhibition increases GH and improves glucose levels and vascular function in women with PCOS. Eighteen women with PCOS participated in a double-blind, crossover study. They received sitagliptin either 100 mg or placebo daily for 1 month, with crossover treatments separated by an 8-week washout. During each treatment, women underwent a 75-gram oral glucose tolerance test (OGTT) and assessments of vascular function and body composition. Overnight GH secretion was assessed via venous sampling every 10 minutes for 12 hours and analyzed using an automated deconvolution algorithm. During OGTT, sitagliptin increased glucagon-like peptide-1 (P < 0.001), early insulin secretion (from mean [± SD] insulinogenic index 1.9 ± 1.2 to 3.2 ± 3.1; P = 0.02), and decreased peak glucose (mean -17.2 mg/dL [95% CI, -27.7 to -6.6]; P < 0.01). At 1 month, sitagliptin decreased VAT (from 1141.9 ± 700.7 to 1055.1 ± 710.1 g; P = 0.02) but did not affect vascular function. Sitagliptin increased GH half-life (from 13.9 ± 3.6 to 17.0 ± 6.8 min, N = 16; P = 0.04) and interpulse interval (from 53.2 ± 20.0 to 77.3 ± 38.2 min, N = 16; P < 0.05) but did not increase mean overnight GH (P = 0.92 vs placebo). Sitagliptin decreased the maximal glucose response to OGTT and VAT. Sitagliptin did not increase overnight GH but increased GH half-life and the interpulse interval. This study was registered at www.clinicaltrials.gov as NCT02122380 prior to enrollment of the first participant.

HDL Cholesterol Efflux Predicts Incident New-Onset Diabetes After Transplantation (NODAT) in Renal Transplant Recipients Independent of HDL Cholesterol Levels.

In renal transplant recipients (RTRs), new-onset diabetes after transplantation (NODAT) is a frequent and serious complication limiting survival of graft and patient. However, the underlying pathophysiology remains incompletely understood. In vitro and in preclinical models, HDL can preserve β-cell function, largely by mediating cholesterol efflux, but this concept has not been evaluated in humans. This study investigated whether baseline cholesterol efflux capacity (CEC) in RTRs is associated with incident NODAT during follow-up. This prospective longitudinal study included 405 diabetes-free RTRs with a functioning graft for >1 year. During a median (interquartile range) follow-up of 9.6 (6.6-10.2) years, 57 patients (14.1%) developed NODAT. HDL CEC was quantified using incubation of human macrophage foam cells with apolipoprotein B-depleted plasma. Baseline CEC was significantly lower in patients developing NODAT during follow-up (median 6.84% [interquartile range 5.84-7.50%]) compared with the NODAT-free group (7.44% [6.46-8.60%]; P = 0.001). Kaplan-Meier analysis showed a lower risk for incident NODAT with increasing sex-stratified tertiles of HDL efflux capacity (P = 0.004). Linear regression analysis indicated that CEC is independently associated with incident NODAT (P = 0.04). In Cox regression analyses, CEC was significantly associated with NODAT (hazard ratio 0.53 [95% CI 0.38-0.76]; P < 0.001), independent of HDL cholesterol levels (P = 0.015), adiposity (P = 0.018), immunosuppressive medication (P = 0.001), and kidney function (P = 0.01). Addition of CEC significantly improved the predictive power of the Framingham Diabetes Risk Score (P = 0.004). This study establishes HDL CEC as a strong predictor of NODAT in RTRs, independent of several other recognized risk factors.

Effect of methyl tert-butyl ether on adipogenesis and glucose metabolism in vitro and in vivo

Methyl tert-butyl ether (MTBE), as a widely used gasoline additive, is suspected of being environmentally toxic. MTBE accumulates mainly in adipose tissue, but its effect on obesity or obesity-related metabolic disorders has not been well understood yet. Therefore, we examined the effect of MTBE on the adipose function and the related metabolic processes with both 3T3-L1 cell line and C57BL/6J mice model. We found that exposure to MTBE at the environmental relevant concentration (100 μmol/L) could significantly induce differentiation of preadipocyte and disturb insulin-stimulated glucose uptake of mature adipocyte. The in vivo observation in male mice showed a positive correlation of visceral white adipose tissue (vWAT) expansion and cell size increase with MTBE treatment in 14 weeks. Glucose tolerance and insulin sensitivity tests demonstrated that MTBE at 1000 μg/(kg·day) disturbed the systemic glucose metabolism in a gender-specific manner, which might be partly attributed to the alterations of gut microbiota community at genus level with respect to Akkermansia, Clostridium XlVb, and Megamonas. In summary, our study characterized the effect of MTBE on adipose tissue function and glucose homeostasis in vitro and in vivo, and revealed that systemic disorders of the glucose metabolism might be modulated by the related gut microbiota.

Elemental Analysis of Aging Human Pituitary Glands Implicates Mercury as a Contributor to the Somatopause.

Background: Growth hormone levels often decline on aging, and this “somatopause” is associated with muscle and bone loss, visceral adiposity and impaired cardiovascular function. Mercury has been detected in human pituitary glands, so to see if mercury could play a part in the somatopause we measured the proportion of people at different ages who had mercury in their anterior pituitary cells.Materials and methods: Paraffin sections of pituitary glands taken at autopsy from 94 people between the ages of 2 and 99 years were stained for inorganic mercury using autometallography. Pituitary mercury content was classified as none, low (<30% of cells) or high (>30% of cells) in increasing two-decade age groups. Autometallography combined with immunohistochemistry determined which hormone-producing cells contained mercury. Laser ablation-inductively coupled plasma-mass spectrometry was used to confirm the presence of mercury.Results: The proportion of people with low-content pituitary mercury remained between 33 and 42% at all ages. The proportion of people with high-content mercury increased with increasing age, from 0% of people in the 2–20 year group to a peak of 50% of people in the 61–80 years group, followed by a fall to 35% of people in the 81–99 years group. Mercury, when present, was found always in somatotrophs, occasionally in corticotrophs, rarely in thyrotrophs and gonadotrophs, and never in lactotrophs. Laser ablation-inductively coupled plasma-mass spectrometry detected mercury in regions of pituitaries that stained with autometallography.Conclusions: The proportion of people with mercury in their anterior pituitary cells, mostly somatotrophs, increases with aging, suggesting that mercury toxicity could be one factor contributing to the decline in growth hormone levels found in advancing age.

Effect of Weight Loss on Physical Function in Overweight and Obese Individuals

Impaired physical function is a major health concern in obesity across the adult life-span. Reducing weight and improving body composition may be critical for improving physical function in overweight and obese adults. PURPOSE: Investigate physical function before and during weight loss and study the relationships of body composition with changes in physical function. METHODS: Data were obtained from women (n=127, age 49.3±12.8 years; weight 101.8±17.9 kg; BMI 37.8±6.6 kg/m2) and men (n=17, age 54.4±10.1 years; weight 131.9±31.9 kg; BMI 40.5±9.9 kg/m2) enrolled in a medical supervised comprehensive weight loss program at Wake Forest Baptist Health Weight Management Center. Mean follow up was 6.7 months. Body composition, grip strength, gait speed, chair rise time, and submaximal VO2max were determined before and at the end of follow-up. Paired samples t-tests analyzed changes between baseline and follow-up. Pearson correlations examined relationships between pre-and-post functional performance tests and fat free mass (FFM), and fat mass (FM). RESULTS: Mean weight loss was 11.8±9.8 kg. Approximately 74.9% of weight loss was from fat mass: [FM (48.3±18.5 kg at baseline and 38.9±12.7 kg at follow-up, p<.001) and FFM (57.9±10.6 kg at baseline and 55.7±10.9 kg at follow-up, p<.001)]. Grip strength (29.3±8.1 to 32.9±11.2 kg, p<.001), chair rise time (9.1±2.9 to 7.8±2.7 s, p=.018), gait speed (1.2±0.2 to 1.3±0.2 m/s, p=.001), and submaximal VO2,max (32.7±3.9 to 34.7±4.5 ml/kg/min, p<.001) all improved from baseline to follow-up, respectively. Gait speed (r= -.292, p=.005) grip strength (r= -.215, p=.041) and chair rise (r= -.273, p=.009) changes were correlated with FM changes but not FFM changes. CONCLUSIONS: A comprehensive weight loss generally improves physical function. This improvement is possibly mediated by FM losses rather than FFM changes.

270-OR: Adipocyte Integrin-Linked Kinase Is Necessary for the Development of Diet-Induced Adipose Insulin Resistance

The remodeling of the extracellular matrix (ECM) in tissues including adipose tissue, and the expression of collagen binding integrin α2β1 have been associated with the development of insulin resistance. Integrin-linked Kinase (ILK), an adaptor protein and a key component of the IPP (ILK-Parvin-PINCH) complex mediates integrins linking the ECM with intracellular signalling. This study determines the role of ILK in adipose function and insulin resistance in chow and high fat (HF)-fed mice. HF feeding increased adipose ILK expression in mice (2.7 ±0.62 vs. 1±0.23; p=0.01). Adipocyte-specific deletion of ILK resulted in a decrease in fat mass (21.6±1.6% vs. 27.3±1.4%; p=0.009) and epididymal tissue weight (eWAT) (1.04±0.07g vs. 1.62±0.11g; p&amp;lt;0.001) in HF-fed mice, but not in chow-fed mice. During the hyperinsulinemic-euglycemic clamp, HF-fed ILK deficient mice showed increased glucose uptake (66.22±p=0.028) in the brown adipose tissue (BAT) compared with the wild type littermate controls. Increased glucose uptake in BAT is associated with increased phosphorylation of AKT (1.96±0.16 vs. 1±0.28 fold change; p=0.01), and decreased phosphorylation of p38 and JNK (0.23 ± 0.17 vs. 1±0.48; p=0.024 and 0.41 ±0.12 vs. 1±0.17; p=0.025 respectively). The inhibition of lipolysis by insulin was also improved in HF-fed ILK deficient mice determined by plasma NEFA level during the clamp. This could be attributed to decreased cell size (0.85±0.042 vs. 1±0.06; p=0.0001), decreased collagen deposition (22.8±0.98 vs. 30.28± 2.05; p=0.01) and a trend increase in vascularization (3.47±1.26 vs. 1±0.23; p=0.07) in the eWAT. These data suggest that adipocyte ILK plays an important role in regulating adipocyte morphology, signaling and glucose and lipid homeostasis, therefore representing a potential target for obesity, insulin resistance and diabetes. Disclosure A. Bugler-Lamb: None. C. Hennayake: None. A. Hasib: None. M.L. Ashford: None. L. Kang: None. Funding Diabetes UK; Diabetes Research &amp; Wellness Foundation

733-P: Circulating Vaspin Level Was Changed with Endothelial Function, but Not with Visceral or Ectopic Fat during Lifestyle Modification in Korean Type 2 Diabetes

Vaspin is an adipocytokine identified in visceral adipose tissues and has anti-inflammatory effects in vascular smooth muscle cells. We investigated the association between visceral or ectopic adiposity, insulin resistance, inflammatory markers and endothelial function including circulating vaspin, and the effects of lifestyle modification in Korean type 2 diabetes. Total 170 overweight women with type 2 diabetes (age 55.0±7.6 years; BMI 27.4±2.8 kg/m2) were randomly assigned to control (C), diet (D), aerobic exercise (AE) and resistance exercise (RE) and 82 completed the weight loss program for 12 weeks. We assessed BMI, total abdominal (TAF), visceral fat (VAF), liver and spleen attenuation ratio (LSR), and intramuscular adipose tissue (IMAT) at midthigh level using computed tomography, and FMD (Flow-mediated dilation), vaspin, adiponectin/leptin ratio (ALR), free fatty acid (FFA), hsCRP, and insulin sensitivity by homeostatic model assessment insulin resistance (HOMA-IR) at baseline, and 12 week. The log transformed variables are prefixed by 'ln' BMI decreased by 7.07% in RE, 6.42% in D and 3.28% in AE (p&amp;lt;0.001 vs. control). TAF and VAF also decreased by 18.82% and 22.06% in RE, 11.96% and 14.12% in D, 8.30%and 8.38% in D (consecutively, p&amp;lt;0.001 vs. control). ALR was increased comparably in 3 intervention groups. Percent changes (pc) of vaspin, FFA, hsCRP, HOMA IR, FMD, IMAT, LSR were not different among 4 groups. Within group analysis, vaspin was increased from 0.74 to 1.04 (p=0.096) in AE, FMD was increased in D and AE (p&amp;lt;0.001, P=0.035). Crushed the groups, ln-vaspin pc was changed with ln-FMD pc (r=-0.246, p=0.016), but not with pc of ln-VAF, IMAT. Total fat was changed with ALR (r=-0.151, p=0.042). LSR with hsCRP (r=-0.217, p=0.038). These findings suggested that the circulating vaspin level was more related with vascular function rather than regional or ectopic adiposity during lifestyle modification in type 2 diabetes. Disclosure K. Han: None. K. Min: None.

1009-P: The Dual GIP and GLP-1 Receptor Agonist Tirzepatide Regulates Lipid and Carbohydrate Metabolism through GIPR in Adipose Tissue

Tirzepatide (TZP), a GIP receptor and GLP-1 receptor (GIPR/GLP-1R) dual agonist, has demonstrated profound effects on glycemic control and bodyweight lowering in T2D subjects. However, the mechanism of action for the dual agonism of TZP is incompletely understood. Adipose expresses GIPR but not GLP-1R and therefore presents a key target tissue to investigate TZP biology. Using differentiated human adipocytes, we explored TZP regulation of lipid and carbohydrate metabolism. TZP demonstrated significant modulation of lipid accumulation, efflux, and oxidation. Similar to insulin, TZP increased expression and secretion of active LPL. While it had no effect on its own, TZP dose dependently suppressed insulin stimulated de novo lipogenesis in [14C]glucose and [14C]acetate incorporation assays. Insulin and TZP counter-regulated lipolysis characterized by insulin suppression and TZP stimulation of glycerol release. Uncoupled oxygen consumption was increased by TZP and subsequently reduced by CPT1 inhibition (etomoxir) demonstrating regulation of fatty acid oxidation. In adipose glycemic control, TZP exhibited both direct and insulin-dependent regulation of glucose transport. TZP at low dose (10pM) provided indirect (insulin sensitizing) effects while higher doses (10 nM) directly stimulated [14C]glucose uptake in adipocytes. While acute GIP infusion in a rat hyperinsulinemic/euglycemic clamp demonstrated no change in total body glucose infusion rate (GIR), chronic treatment (two week) with TZP or GIPR agonist increased GIR and adipose tissue [14C]glucose accumulation. This suggests both tissue-specific and whole-body insulin sensitization through GIPR agonism. Taken together, this data demonstrates GIPR specific activity of TZP in regulating adipose function. These findings and ongoing pathway integration studies will provide clues to the metabolic benefit of TZP GIPR/GLP-1R dual agonism compared with GLP-1R agonism alone. Disclosure R.J. Samms: Employee; Self; Eli Lilly and Company. M.E. Christe: Employee; Self; Eli Lilly and Company. X. Ruan: Employee; Self; Eli Lilly and Company. J. Moyers: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. A. Regmi: Employee; Self; Eli Lilly and Company. W.C. Roell: Employee; Self; Eli Lilly and Company.

Neuroendocrine Regulation of Energy Metabolism Involving Different Types of Adipose Tissues.

Despite tremendous research efforts to identify regulatory factors that control energy metabolism, the prevalence of obesity has been continuously rising, with nearly 40% of US adults being obese. Interactions between secretory factors from adipose tissues and the nervous system innervating adipose tissues play key roles in maintaining energy metabolism and promoting survival in response to metabolic challenges. It is currently accepted that there are three types of adipose tissues, white (WAT), brown (BAT), and beige (BeAT), all of which play essential roles in maintaining energy homeostasis. WAT mainly stores energy under positive energy balance, while it releases fuels under negative energy balance. Thermogenic BAT and BeAT dissipate energy as heat under cold exposure to maintain body temperature. Adipose tissues require neural and endocrine communication with the brain. A number of WAT adipokines and BAT batokines interact with the neural circuits extending from the brain to cooperatively regulate whole-body lipid metabolism and energy homeostasis. We review neuroanatomical, histological, genetic, and pharmacological studies in neuroendocrine regulation of adipose function, including lipid storage and mobilization of WAT, non-shivering thermogenesis of BAT, and browning of BeAT. Recent whole-tissue imaging and transcriptome analysis of differential gene expression in WAT and BAT yield promising findings to better understand the interaction between secretory factors and neural circuits, which represents a novel opportunity to tackle obesity.

143-OR: Illuminating Ldb1 as a Novel Transcriptional Regulator of Brown Adipose Function

Brown adipose tissue (BAT) is critical for thermogenesis and glucose/lipid homeostasis. BAT utilizes fatty acids and glucose for heat production via mitochondrial uncoupling, and is thus an attractive therapeutic target for combatting obesity. Expanding the energy uncoupling capacity of this tissue requires a greater understanding of underlying BAT transcriptional mechanisms. We recently reported on a transcriptional co-regulator, LIM domain binding protein 1 (Ldb1), which appears to have novel roles in BAT biology. Ldb1 acts as a dimerized scaffold allowing for the assembly of transcriptional complexes and is important for the development and function of many metabolic tissues, including the brain and pancreatic islets. However, roles for BAT-expressed Ldb1 have not been elucidated. We set out to test the hypothesis that Ldb1 directly impacts BAT development and function. Our in vitro studies have shown that primary brown adipocytes lacking Ldb1 have reductions in BAT-selective genes including Ucp1 and Elovl3 and are unable to induce Ucp1 expression upon agonist treatment, a result similarly observed in the X9 Ucp1-expressing cell line. To test Ldb1 roles in vivo, we developed a mouse model, termed Ldb1ΔBAT, in which Ldb1 was reduced in thermogenic adipocytes using a Ucp1-driven Cre recombinase. The Ldb1ΔBAT mice were cold intolerant during a cold challenge, which is supportive of thermogenic defects in the Ldb1-deficient tissue. The knockout mice were also glucose intolerant via intraperitoneal glucose challenge and preliminary data suggest insulin insensitivity, via intraperitoneal insulin tolerance test. Histological analyses of Ldb1ΔBAT BAT depots indicated an alteration in brown adipocyte morphology and potentially intercellular lipid content, suggesting cellular dysfunction. Overall, this work indicates that Ldb1 has a direct role in maintaining thermogenic and metabolic function in BAT. Disclosure J. Kepple: None. Y. Liu: None. C.S. Hunter: None.

Adipokinome Signatures in Obese Mouse Models Reflect Adipose Tissue Health and Are Associated with Serum Lipid Composition.

Adipocyte and hepatic lipid metabolism govern whole-body metabolic homeostasis, whereas a disbalance of de novo lipogenesis (DNL) in fat and liver might lead to obesity, with severe co-morbidities. Nevertheless, some obese people are metabolically healthy, but the “protective” mechanisms are not yet known in detail. Especially, the adipocyte-derived molecular mediators that indicate adipose functionality are poorly understood. We studied transgenic mice (alb-SREBP-1c) with a “healthy” obese phenotype, and obob mice with hyperphagia-induced “sick” obesity to analyze the impact of the tissue-specific DNL on the secreted proteins, i.e., the adipokinome, of the primary adipose cells by label-free proteomics. Compared to the control mice, adipose DNL is reduced in both obese mouse models. In contrast, the hepatic DNL is reduced in obob but elevated in alb-SREBP-1c mice. To investigate the relationship between lipid metabolism and adipokinomes, we formulated the “liver-to-adipose-tissue DNL” ratio. Knowledge-based analyses of these results revealed adipocyte functionality with proteins, which was involved in tissue remodeling or metabolism in the alb-SREBP-1c mice and in the control mice, but mainly in fibrosis in the obob mice. The adipokinome in “healthy” obesity is similar to that in a normal condition, but it differs from that in “sick” obesity, whereas the serum lipid patterns reflect the “liver-to-adipose-tissue DNL” ratio and are associated with the adipokinome signature.

Glucose Abnormalities Associated to Prolactin Secreting Pituitary Adenomas.

The pathogenesis of obesity and alterations in glucose profile have been linked to PRL excess, as it is reportedly associated with metabolic syndrome in thereabout one third of patients. In vitro exposure of pancreatic islet to PRL is known to stimulate insulin secretion and β-cell proliferation, and in turn overexpression of PRL in β-cells increases insulin release and β-cell replication. PRL excess has been found to worsen glucose profile because it reduces glucose tolerance and induces insulin resistance either in obese and non-obese patients. To note, pancreatic β-cells and adipocytes widely express dopamine receptors type 2, and dopamine has been hypothesized to play a key role as modulator of insulin and adipose functions. The dopamine agonists bromocriptine and cabergoline significantly improve abnormalities in glucose profile and reduce the prevalence of metabolic syndrome in a remarkable proportion of patients, regardless of whether body weight and PRL status may change. However, in men with hyperprolactinemia complicated by hypogonadism, testosterone replacement can ameliorate insulin resistance and abnormalities in glucose metabolism. Therefore, in patients with PRL-secreting pituitary adenomas control of PRL excess by dopamine agonists is mandatory to improve glucose and insulin abnormalities.

The association of thyroid-stimulating hormone (TSH) and free thyroxine (fT4) concentration levels with carbohydrate and lipid metabolism in obese and overweight teenagers.

Obesity has increased rapidly among children and adolescents during the last 30 years. Paediatric patients with a BMI above the 85th centile are more often diagnosed with increased TSH levels than are children with proper body weight. The data of 961 overweight and obese children, aged 13 years, recruited in four cities in Poland as part of PoZdro!, a two-year prophylactic program, were analysed to observe the relationship between serum TSH and fT4 concentration and carbohydrate and lipid metabolism parameters, as well as anthropometric parameters. TSH concentration in the study group was positively correlated, whereas fT4 concentration was negatively correlated with WHR and WHtR values, fasting serum glucose concentrations and one-hour glucose concentration, fasting serum insulin concentrations, one-hour and two-hour insulin concentration, ALT serum activity, as well as total cholesterol, LDL cholesterol, and triglyceride serum concentrations. An increased risk of metabolic syndrome was diagnosed previously in patients with TSH concentrations > 2.5 mUI/L. TSH concentration in the upper half of the current reference range (> 2.50 mIU/L) is associated with an increased risk of lipid and carbohydrate metabolism disorders and therefore increased chances of developing metabolic syndrome. It seems advisable to regularly monitor thyroid function in overweight and obese paediatric patients.

Inflammatory cytokines mediate the effects of diet and exercise on pain and function in knee osteoarthritis independent of BMI

Diet restriction and exercise form key treatments for osteoarthritis (OA) related symptoms in overweight and obese individuals. Although both interventions are known to influence systemic low-grade inflammation, which is related to pain levels and functional limitations, little is known about the potential changes in systemic inflammation as a working mechanism of diet restriction and exercise in knee OA. Data from the Arthritis, Diet, and Activity Promotion Trial (ADAPT) were used. Through causal mediation analyses, the proportion of the effect of a 18 months diet and exercise intervention explained by the 18 months change in interleukin (IL)-6, TNF-α, soluble IL-6 receptor, soluble IL-1 receptor, CRP, and BMI were assessed, using self-reported pain and function as outcomes. The change in inflammatory factors accounted for 15% of the total effect on pain and was totally independent of the change in BMI. The change in inflammatory factors accounted for 29% of the effect on function, with the change in BMI adding only 4% to the total mediated effect. The change in inflammatory factors after the diet and exercise intervention was a 'medium' size mediator of the effect on pain and a 'strong' mediator for the effect on function in overweight and obese individuals with knee OA. The change in BMI added minimally to the mediated effect on function. These results highlight the relevance of changes in systemic inflammation as drivers for clinically relevant effects after diet and exercise in overweight and obese individuals with knee OA.

MON-474 Dipeptidyl Peptidase-4 (DPP4) Inhibition Decreases Visceral Fat and Improves Glucose Metabolism in Overweight Women with Polycystic Ovarian Syndrome

Background: Women with PCOS have decreased GH secretion.1 Diminished GH is associated with increased visceral adiposity and impaired vascular function. GH releasing hormone is the primary stimulus for GH secretion and a substrate of dipeptidyl peptidase-4 (DPP4).2 We tested the hypothesis that one month of DPP4 inhibition with sitagliptin increases GH secretion and improves glucose metabolism and vascular function in women with PCOS. Methods: Eighteen women with PCOS (BMI ≥ 25 kg/m2) participated in a randomized, double-blinded, cross-over study during which they received sitagliptin 100 mg p.o. vs. placebo daily for one month separated by a minimum eight-week wash-out. At two weeks, women underwent a 75 g oral glucose tolerance test (OGTT). At one month, women were admitted for fasting laboratories, assessment of conduit artery vascular function, and measurement of body composition via DEXA. Overnight GH secretion was assessed using an automated deconvolution algorithm (AutoDecon) previously validated for the analysis of endogenous pulsatile GH secretion from time-series data obtained via frequent venous sampling from an indwelling catheter every ten minutes for twelve hours. Results: Sitagliptin 100 mg daily decreased DPP4 activity (p<0.001 vs. placebo) and increased GLP-1 levels (p<0.001 vs. placebo) during OGTT. Glucose metabolism improved during sitagliptin, as demonstrated by mean decrease in blood glucose of 15.4 mg/dL (95% CI 8.7, 22.1; p<0.001) at 100 minutes as compared to placebo. Sitagliptin enhanced early insulin secretion (from mean insulinogenic index 1.9 ± SD 1.2 to 3.2 ± 3.1; p=0.01). At one month, sitagliptin decreased visceral adipose tissue (VAT) (from 1141.9 g ± 700.7 to 1055.1 ± 710.1; p=0.02) and total cholesterol (from 168.8 mg/dL ± 26.3 to 162.5 ± 22.2; p=0.02) but did not affect vascular function. Sitagliptin did not increase overnight GH secretion, as summarized by area over the curve (AUC) or mean GH, but did increase GH half-life (from 13.9 min ± 3.6 to 16.8 ± 6.2, N=16; p=0.04) and the interpulse interval (from 53.2 min ± 20.0 to 77.3 ± 38.4, N=16; p<0.05). DPP4 activity levels during sitagliptin were associated with overnight GH secretion (GH AUC: rs= -0.60, p=0.01; mean GH: rs= -0.57, p=0.02), VAT mass (rs= 0.66; p<0.01), and insulin resistance (HOMA-IR rs=0.54; p=0.04). Conclusions: Sitagliptin improved blood glucoses following 75 g OGTT in overweight women with PCOS and decreased VAT but did not enhance vascular function. While sitagliptin did not increase overnight GH secretion, it did enhance GH half-life and the interpulse interval. Moreover, the response to sitagliptin was directly related to overnight GH secretion and inversely to VAT and insulin resistance. In this pilot study, sitagliptin improved glucose metabolism and body composition in accordance with GH secretion. 1 deBoer et al., Hum. Reprod. 2004 19: 504. 2 Frohman et al., J Clin Invest. 1986 78:906.

Effect of fitness on cardiac structure and function in overweight and obesity (the FATCOR study)

Background and aimsObesity is associated with reduced left ventricular (LV) systolic myocardial function. We aimed to explore by means of a cross-sectional study whether this effect is offset in the presence of good fitness. Methods and resultsWe studied clinical and echocardiographic data from 469 overweight (body mass index [BMI] >27 kg/m2) and obese (BMI ≥30 kg/m2) women and men without known cardiovascular (CV) disease in the FAT associated CardiOvasculaR dysfunction (FATCOR) study. The participants were grouped according to obesity and sex- and age adjusted peak oxygen uptake, obtained by ergospirometry. LV systolic myocardial function was assessed by peak systolic global longitudinal strain (GLS) measured by speckle tracking echocardiography. The association of fitness with GLS was tested in logistic regression analyses and reported as odds ratio (OR) with 95% confidence interval (CI).In the total study population, participants were 47 years old, 60% were women, and mean BMI was 32.0 kg/m2. GLS did not differ between fit and unfit subjects within the overweight and obese groups (both p > 0.05), but the overweight fit group had higher GLS (more negative value) compared to the obese unfit group (−20.1 ± 2.6 vs. −19.0 ± 3.0, p < 0.05). In obese subjects, fitness was associated with higher GLS (OR 0.88 [95% CI 0.79–0.99, p < 0.05) in multivariable logistic regression analysis, independent of significant associations with higher arterial stiffness and lower fat percentage (all p < 0.05). In the overweight group, fitness was not significantly associated with GLS. ConclusionIn obesity, fitness was independently associated with higher GLS, while no association was found in overweight. Clinical trial registrationURL: http://www.clinicaltrials.govNCT02805478.

Regulation of nicotinic acetylcholine receptor α3 subtype in adipose tissue dysfunction

Nicotinic acetylcholine receptor α3 subtype (α3-nAChR) plays a pivotal role in regulating inflammatory responses. Inflammation leads to the adipose tissue dysfunction and further increases the risk of metabolic and cardiovascular diseases. Therefore, we hypothesize that α3-nAChR could regulate the disorder of adipose functions. Adipocytokines and inflammatory cytokines were evaluated in apolipoprotein E knockout (ApoE−/−) mice after α3-nAChR was antagonized and in adipocytes after α3-nAChR gene was silenced. Results showed that in high fat diet-fed ApoE−/− mice with α3-nAChR blocked and in IL-6-stimulated adipocytes with α3-nAChR gene silenced the productions of leptin, resistin, triglyceride, cholesterol and low density lipoprotein were significantly increased but the generations of adiponectin and high density lipoprotein were markedly deceased. Meanwhile, the release of inflammatory cytokines was notably augmented. Moreover, the activation of JAK2/STAT3 was involved in the α3-nAChR-dependent signaling pathways in the regulation of adipose tissue dysfunction. A way may be paved for further investigations for the regulatory role of α3-nAChR in inflammatory and metabolic diseases.

Vascular Modulation of Adipose function: Role of Endothelial Argonaute 1

Among all individuals with Type 2 diabetes mellitus (T2DM), 80% are obese. The dramatic expansion of adipocytes can give rise to chronic hypoxia, poor blood perfusion, accumulation of pro‐inflammatory cytokines, all of which contribute to insulin resistance, key feature of T2DM. Lining the inner surface of microvessels, endothelial cells (ECs) respond to alterations in oxygen, metabolites, and growth factors to further modulate adipose function. However, the molecular and cellular mechanisms underlying the EC‐adipose crosstalk remain largely unknown and have recently attracted great research interests. In this study, we investigated the role of microvascular ECs in adipose function in the context of obesity and insulin resistance. Specifically, we examined the role of microRNA (miR)‐mediated gene regulation in the endothelial modulation of adipose function.We first used cross‐linking and immunoprecipitation sequencing (CLIP‐seq) to profile the miR targetome in ECs subjected to hypoxia, to which the EC response is often compromised in obesity. CLIP‐seq revealed a panel of angiogenic inhibitors, including thrombospondin‐1 (THBS1; which is positively associated with obesity and insulin resistance) were enriched in miR‐induced silencing complex in ECs under hypoxia. However, their expression was drastically suppressed in ECs by hypoxia. Ina murine T2DM model, mice with EC‐specific AGO1‐knockout (EC‐AGO1‐KO) exhibited a lean phenotype, with lower body weight and fasting glucose level and higher insulin sensitivity, as compared to their wild‐type littermates. The EC‐AGO1‐KO animals also had less body fat content, particularly in the subcutaneous and brown adipose tissues. Histological analysis and RNA‐seq demonstrated that EC‐AGO1‐KO possess higher angiogenic and browning activity and lower inflammation in the adipose depots. Overexpression of THBS1 abolished the protective effect of AGO1 in the subcutaneous tissues, suggesting that AGO1‐KO‐mediated metabolic benefit is in part through suppression of THBS1.Collectively, these results support a mechanism by which ECs, through AGO1‐mediated miR‐targetome modulate adipose function and metabolic states. Our study provides novel insights linking endothelial function and adipose tissue remodeling. Further, given that endothelial function is often compromised in T2DM, the molecular mechanisms underlying the endothelium‐adipocyte crosstalk may offer new approach to manage metabolic disruption associated with obesity and diabetes.Support or Funding InformationK99/R00HL122368This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Assembling the adipose organ: adipocyte lineage segregation and adipogenesis in vivo.

Adipose tissue is composed of anatomically distinct depots that mediate several important aspects of energy homeostasis. The past two decades have witnessed increased research effort to elucidate the ontogenetic basis of adipose form and function. In this Review, we discuss advances in our understanding of adipose tissue development with particular emphasis on the embryonic patterning of depot-specific adipocyte lineages and adipocyte differentiation in vivo Micro-environmental cues and other factors that influence cell identity and cell behavior at various junctures in the adipocyte lineage hierarchy are also considered.

Resistance to visceral obesity is associated with increased locomotion in mice expressing an endothelial cell-specific fibroblast growth factor 1 transgene.

Overdevelopment of visceral adipose is positively correlated with the etiology of obesity‐associated pathologies including cardiovascular disease and insulin resistance. However, identification of genetic, molecular, and physiological factors regulating adipose development and function in response to nutritional stress is incomplete. Fibroblast Growth Factor 1 (FGF1) is a cytokine expressed and released by both adipocytes and endothelial cells under hypoxia, thermal, and oxidative stress. Expression of Fibroblast Growth Factor 1 (FGF1) in adipose is required for normal depot development and remodeling. Loss of FGF1 leads to deleterious changes in adipose morphology, metabolism, and insulin resistance. Conversely, diabetic and obese mice injected with recombinant FGF1 display improvements in insulin sensitivity and a reduction in adiposity. We report in this novel, in vivo study that transgenic mice expressing an endothelial‐specific FGF1 transgene (FGF1‐Tek) are resistant to high‐fat diet‐induced abdominal adipose accretion and are more glucose‐tolerant than wild‐type control animals. Metabolic chamber analyses indicate that suppression of the development of visceral adiposity and insulin resistance was not associated with alterations in appetite or resting metabolic rate in the FGF1‐Tek strain. Instead, FGF1‐Tek mice display increased locomotor activity that likely promotes the utilization of dietary fatty acids before they can accumulate in adipose and liver. This study provides insight into the impact that genetic differences dictating the production of FGF1 has on the risk for developing obesity‐related metabolic disease in response to nutritional stress.