Glucose Uptake In Adipose Tissue Research Articles

The thermoneutral zone in women takes an “arctic” shift compared to men

Conventionally, women are perceived to feel colder than men, but controlled comparisons are sparse. We measured the response of healthy, lean, young women and men to a range of ambient temperatures typical of the daily environment (17 to 31 °C). The Scholander model of thermoregulation defines the lower critical temperature as threshold of the thermoneutral zone, below which additional heat production is required to defend core body temperature. This parameter can be used to characterize the thermoregulatory phenotypes of endotherms on a spectrum from "arctic" to "tropical." We found that women had a cooler lower critical temperature (mean ± SD: 21.9 ± 1.3 °C vs. 22.9 ± 1.2 °C, P = 0.047), resembling an "arctic" shift compared to men. The more arctic profile of women was predominantly driven by higher insulation associated with more body fat compared to men, countering the lower basal metabolic rate associated with their smaller body size, which typically favors a "tropical" shift. We did not detect sex-based differences in secondary measures of thermoregulation including brown adipose tissue glucose uptake, muscle electrical activity, skin temperatures, cold-induced thermogenesis, or self-reported thermal comfort. In conclusion, the principal contributors to individual differences in human thermoregulation are physical attributes, including body size and composition, which may be partly mediated by sex.

A Randomized Trial of the Efficacy of Three Weight Loss Diet Interventions in Overweight/Obese with Polycystic Ovary Syndrome

Background: Polycystic Ovary Syndrome (PCOS) is a highly prevalent, complex, heterogeneous, polygenic endocrine disorder characterized by metabolic and reproductive dysfunction that affects 8-13% of women of reproductive age worldwide. The pathogenesis of PCOS has not been fully clarified and includes genetics, obesity, and insulin resistance (IR). Oxidative stress (OS) of PCOS is independent of obesity. It can induce IR through post-insulin receptor defects, impair glucose uptake in muscle and adipose tissue, and exacerbate IR by reducing insulin secretion from pancreatic β-cells. Objective: To investigate the effects of Calorie Restricted Diet (CRD), High Protein Diet (HPD), and High Protein and High Dietary Fiber Diet (HPD+HDF) on body composition, insulin resistance, and oxidative stress in overweight/obese PCOS patients. Methods: A total of 90 overweight/obese patients with PCOS were selected to receive an 8- week medical nutrition weight loss intervention at our First Hospital of Peking University, and we randomly divided them into the CRD group (group A), the HPD group (group B), and the HPD+HDF group (group C), with 30 patients in each group. We measured their body composition, HOMA-IR index, and oxidative stress indicators. The t-test, Mann-Whitney U test, analysis of variance (ANOVA), and Kruskal-Wallis H test were used to compare the efficacy of the three methods. Results: After eight weeks, the body weights of the three groups decreased by 6.32%, 5.70% and 7.24%, respectively, and the Visceral Fat Area (VFA) values decreased by 6.8cm2, 13.4cm2 and 23.45 cm2, respectively, especially in group C (p <0.05). The lean body mass (LBM), also known as the Fat-Free Mass (FFM) values of group B and group C after weight loss, were higher than that of group A (p <0.05). After weight loss, the homeostatic model assessment of insulin resistance (HOMA-IR) index and malondialdehyde (MDA) were decreased. Superoxide dismutase (SOD) was increased in all three groups (p <0.05), and the changes in SOD and MDA in group B and group C were more significant (p <0.05). HOMA-IR index positively correlated with body mass index (BMI) (r=0.195; p <0.05); MDA positively correlated with percent of body fat (PBF) (r=0.186; p <0.05) and HOMA-IR index (r=0.422; p <0.01); SOD positively correlated with LMI/FFMI (r=0.195; p <0.05), negatively correlated with HOMA-IR index (r=-0.433; p <0.01). Conclusion: All three diets were effective in reducing the body weight of overweight/obese patients with PCOS by more than 5% within 8 weeks and could improve both insulin resistance and oxidative stress damage. Compared with CRD, HPD and HPD+HDF diets could better retain lean body mass and significantly improve oxidative stress damage.

Is the β3-Adrenoceptor a Valid Target for the Treatment of Obesity and/or Type 2 Diabetes?

β3-Adrenoceptors mediate several functions in rodents that could be beneficial for the treatment of obesity and type 2 diabetes. This includes promotion of insulin release from the pancreas, cellular glucose uptake, lipolysis, and thermogenesis in brown adipose tissue. In combination, they lead to a reduction of body weight in several rodent models including ob/ob mice and Zucker diabetic fatty rats. These findings stimulated drug development programs in various pharmaceutical companies, and at least nine β3-adrenoceptor agonists have been tested in clinical trials. However, all of these projects were discontinued due to the lack of clinically relevant changes in body weight. Following a concise historical account of discoveries leading to such drug development programs we discuss species differences that explain why β3-adrenoceptors are not a meaningful drug target for the treatment of obesity and type 2 diabetes in humans.

Higher Plasma Levels of Endocannabinoids and Analogues Correlate With a Worse Cardiometabolic Profile in Young Adults.

The endocannabinoid system (ECS) is a signaling system composed of endocannabinoids (eCBs), their receptors, and the enzymes involved in their synthesis and metabolism. Alterations in the ECS are linked to the development of cardiometabolic diseases. Here, we investigated the relationship between plasma levels of eCBs and their analogues with body composition and cardiometabolic risk factors. The study included 133 young adults (age 22.1 ± 2.2 years, 67% women). Fasting plasma levels of eCBs and their analogues were measured using liquid chromatography-tandem mass spectrometry. Body composition, brown adipose tissue (BAT) volume, glucose uptake, and traditional cardiometabolic risk factors were measured. Plasma levels of eCBs and several eCB analogues were positively correlated with adiposity and traditional cardiometabolic risk factors (eg, serum insulin and triacylglyceride levels, all r ≥ 0.17 and P ≤ .045). Plasma levels of 2-arachidonoyl glycerol and N-pentadecenoylethanolamine were negatively correlated with BAT volume and glucose uptake (all r ≤ -0.17 and P ≤ .047). We observed that the plasma levels of eCBs and their analogues were higher in metabolically unhealthy overweight-obese participants than in metabolically healthy overweight-obese participants. Our findings show that the plasma levels of eCBs and their analogues are related to higher levels of adiposity and worse cardiometabolic profile.

A Propolis-Derived Small Molecule Tectochrysin Ameliorates Type 2 Diabetes in Mice by Activating Insulin Receptor β.

Propolis has been found to decrease glucose levels and increase insulin sensitivity in type 2 diabetes. However, the active ingredient responsible for these effects and its regulating mechanism are not fully understood. To address this, molecular docking screening is used to screen the effective hypoglycemic ingredient in propolis and found that tectochrysin (TEC) has a high affinity to the insulin receptor (IR), highlighting its potential for glycemic control. In vivo tests show that TEC decreases glucose levels and enhances insulin sensitivity in db/db mice. By hyperinsulinemic euglycemic clamp test, this study further finds that TEC promotes glucose uptake in adipose tissue and skeletal muscle, as well as inhibits hepatic gluconeogenesis. Moreover, it finds that TEC promotes glucose uptake and adipocytes differentiation in 3T3-L1 cells like insulin, suggesting that TEC exerts an insulin mimetic effect. Mechanistically, pharmacology inhibition of IRβ abolishes the effects of TEC on glucose uptake and the phosphorylation of IR. The study further demonstrates that TEC binds to and activates IRβ by targeting its E1077 and M1079. Therefore, this study sheds light on the mechanism underlying propolis' potential for ameliorating type 2 diabetes, offering a natural food-derived compound as a promising therapeutic option.

Palmitoleic acid on top of HFD ameliorates insulin resistance independent of diacylglycerols and alters gut microbiota in C57BL/6J mice

With the prevalence of obesity and obesity-related metabolic syndrome, such as insulin resistance in recent years, it is urgent to explore effective interventions to prevent the progression of obesity-related metabolic syndrome. Palmitoleic acid is a monounsaturated fatty acid that is available from dietary sources, mainly derived from marine products. Palmitoleic acid plays a positive role in maintaining glucose homeostasis and reducing inflammation. However, it is still unknow the mechanism of palmitoleic acid in ameliorating insulin resistance. Here, we investigated the effects of palmitoleic acid on chow diet (CD)-fed and high-fat diet (HFD)-fed mice, which were fed CD or HFD for 12 weeks before administration. We administrated mice with BSA (control), oleic acid, or palmitoleic acid for 6 weeks on top of CD or HFD feeding. We found that palmitoleic acid only improved glucose homeostasis in HFD-fed obese mice by increasing glucose clearance and reducing HOMA-IR. Further study explored that palmitoleic acid changed the composition of gut microbiota by decreasing Firmicutes population and increasing Bacteroidetes population. In colon, palmitoleic acid increased intestinal tight junction integrity and reduced inflammation. Moreover, palmitoleic acid decreased macrophage infiltration in liver and adipose tissue and increase glucose uptake in adipose tissue. Diacylglycerol (DAG) in tissue (for example, liver) is found to positively correlated with HOMA-IR. HFD enhanced the levels of DAGs in liver but not in adipose tissue in this study. Palmitoleic acid did not reverse the high DAG levels induced by HFD in liver. Therefore, in HFD-fed mice, palmitoleic acid reduced insulin resistance by an independent-manner of DAGs. It might be associated with the beneficial effects of palmitoleic acid on altering the gut microbiota composition, improving of intestinal barrier function, and downregulating the inflammation in colon, liver, and adipose tissue.

RabGAP AS160/TBC1D4 deficiency increases long-chain fatty acid transport but has little additional effect on obesity and metabolic syndrome in ADMSCs-derived adipocytes of morbidly obese women.

The Akt substrate of 160kDa (AS160), also known as TBC1 domain family member 4 (TBC1D4), represents a crucial regulator of insulin-stimulated glucose uptake in skeletal muscle and adipose tissue. Recent evidence suggests that AS160/TBC1D4 may also control the cellular entry of long-chain fatty acids (LCFAs), resulting in changes to the lipid profile of muscles and fat cells in lean subjects. However, there are virtually no data on AS160/TBC1D4 expression and its modulatory role in lipid metabolism in the adipocytes from morbidly obese individuals of different metabolic status. In this study, we evaluated the effect of the three main factors, i.e., AS160 silencing, obesity, and metabolic syndrome on lipid uptake and profile in fully differentiated adipocytes derived from mesenchymal stem cells (ADMSCs) of lean and obese (with/without metabolic syndrome) postmenopausal women. Additionally, we tested possible interactions between the explanatory variables. In general, obesity translated into a greater content of fatty acid transporters (especially CD36/SR-B2 and SLC27A4/FATP4) and boosted accumulation of all the examined lipid fractions, i.e., triacylglycerols (TAGs), diacylglycerols (DAGs), and free fatty acids (FFAs). The aforementioned were further enhanced by metabolic syndrome. Moreover, AS160 deficiency also increased the abundance of SLC27A4/FATP4 and CD36/SR-B2, especially on the cell surface of the adipocytes derived from ADMSCs of subcutaneous deposit. This was further accompanied by increased LCFA (palmitic acid) uptake. Despite the aforementioned, AS160 silencing seemed unable to significantly affect the phenotype of the adipocytes stemming from obese patients with respect to their cellular lipid profile as we observed virtually no changes in TAG, DAG, and FFA contents when compared to cells with the reference level of proteins. Nevertheless, knockdown of AS160 stimulated fatty acid oxidation, which may indicate that adaptive mechanisms counteract excessive lipid accumulation. At the same time, adipocytes of visceral origin were rather insensitive to the applied intervention.

Hepatic Phospholipid Remodeling Modulates Insulin Sensitivity and Systemic Metabolism.

The liver plays a central role in regulating glucose and lipid metabolism. Aberrant insulin action in the liver is a major driver of selective insulin resistance, in which insulin fails to suppress glucose production but continues to activate lipogenesis in the liver, resulting in hyperglycemia and hypertriglyceridemia. The underlying mechanisms of selective insulin resistance are not fully understood. Here It is shown that hepatic membrane phospholipid composition controlled by lysophosphatidylcholine acyltransferase 3 (LPCAT3) regulates insulin signaling and systemic glucose and lipid metabolism. Hyperinsulinemia induced by high-fat diet (HFD) feeding augments hepatic Lpcat3 expression and membrane unsaturation. Loss of Lpcat3 in the liver improves insulin resistance and blunts lipogenesis in both HFD-fed and genetic ob/ob mouse models. Mechanistically, Lpcat3 deficiency directly facilitates insulin receptor endocytosis, signal transduction, and hepatic glucose production suppression and indirectly enhances fibroblast growth factor 21 (FGF21) secretion, energy expenditure, and glucose uptake in adipose tissue. These findings identify hepatic LPCAT3 and membrane phospholipid composition as a novel regulator of insulin sensitivity and provide insights into the pathogenesis of selective insulin resistance.

A Pilot Study of Neurobiological Mechanisms of Stress and Cardiovascular Risk.

Coronary heart disease is a leading cause of death and disability. Although psychological stress has been identified as an important potential contributor, mechanisms by which stress increases risk of heart disease and mortality are not fully understood. The purpose of this study was to assess mechanisms by which stress acts through the brain and heart to confer increased CHD risk. Coronary Heart Disease patients (N=10) underwent cardiac imaging with [Tc-99m] sestamibi single photon emission tomography at rest and during a public speaking mental stress task. Patients returned for a second day and underwent positron emission tomography imaging of the brain, heart, bone marrow, aorta (indicating inflammation) and subcutaneous adipose tissue, after injection of [18F]2-fluoro-2-deoxyglucose for assessment of glucose uptake followed mental stress. Patients with (N=4) and without (N=6) mental stress-induced myocardial ischemia were compared for glucose uptake in brain, heart, adipose tissue and aorta with mental stress. Patients with mental stress-induced ischemia showed a pattern of increased uptake in the heart, medial prefrontal cortex, and adipose tissue with stress. In the heart disease group as a whole, activity increase with stress in the medial prefrontal brain and amygdala correlated with stress-induced increases in spleen (r=0.69, p=0.038; and r=0.69, p=0.04 respectfully). Stress-induced frontal lobe increased uptake correlated with stress-induced aorta uptake (r=0.71, p=0.016). Activity in insula and medial prefrontal cortex was correlated with post-stress activity in bone marrow and adipose tissue. Activity in other brain areas not implicated in stress did not show similar correlations. Increases in medial prefrontal activity with stress correlated with increased cardiac glucose uptake with stress, suggestive of myocardial ischemia (r=0.85, p=0.004). These findings suggest a link between brain response to stress in key areas mediating emotion and peripheral organs involved in inflammation and hematopoietic activity, as well as myocardial ischemia, in Coronary Heart Disease patients.

Obesity risk is associated with brain glucose uptake and insulin resistance.

To investigate whether alterations in brain glucose uptake (BGU), insulin action in the brain-liver axis and whole-body insulin sensitivity occur in young adults in pre-obese state. Healthy males with either high risk (HR; n = 19) or low risk (LR; n = 22) for developing obesity were studied with [18F]fluoro-d-glucose ([18F]FDG)-positron emission tomography during hyperinsulinemic-euglycemic clamp. Obesity risk was assessed according to BMI, physical activity and parental overweight/obesity and type 2 diabetes. Brain, skeletal muscle, brown adipose tissue (BAT), visceral adipose tissue (VAT) and abdominal and femoral s.c. adipose tissue (SAT) glucose uptake (GU) rates were measured. Endogenous glucose production (EGP) was calculated by subtracting the exogenous glucose infusion rate from the rate of disappearance of [18F]FDG. BGU was analyzed using statistical parametric mapping, and peripheral tissue activity was determined using Carimas Software imaging processing platform. BGU was higher in the HR vs LR group and correlated inversely with whole-body insulin sensitivity (M value) in the HR group but not in the LR group. Insulin-suppressed EGP did not differ between the groups but correlated positively with BGU in the whole population, and the correlation was driven by the HR group. Skeletal muscle, BAT, VAT, abdominal and femoral SAT GU were lower in the HR group as compared to the LR group. Muscle GU correlated negatively with BGU in the HR group but not in the LR group. Increased BGU, alterations in insulin action in the brain-liver axis and decreased whole-body insulin sensitivity occur early in pre-obese state.

Low Bone Turnover Due to Hypothyroidism or Anti-Resorptive Treatment Does Not Affect Whole-Body Glucose Homeostasis in Male Mice.

Bone is a large and dynamic tissue and its maintenance requires high amounts of energy as old or damaged bone structures need to be replaced during the process of bone remodeling. Glucose homeostasis is an essential prerequisite for a healthy bone and vice versa, the skeleton can act as an endocrine organ on energy metabolism. We recently showed that hypothyroidism in mice leads to an almost complete arrest of bone remodeling. Here, we aimed to investigate whether the profound suppression of bone remodeling affects whole-body glucose homeostasis. To that end, male C57BL/6JRj mice were rendered hypothyroid over 4 weeks using methimazole and sodium perchlorate in the drinking water. We confirmed trabecular bone gain due to decreased bone turnover in hypothyroid mice with decreased cortical but increased vertebral bone strength. Further, we found impaired glucose handling but not insulin resistance with hypothyroidism. In hypothyroid bone, glucose uptake and expression of glucose transporter Glut4 were reduced by 44.3% and 13.9%, respectively, suggesting lower energy demands. Nevertheless, hypothyroidism led to distinct changes in glucose uptake in muscle, liver, and epididymal white adipose tissue (eWAT). Reduced glucose uptake (−30.6%) and Glut1/Glut4 transcript levels (−31.9%/−67.5%) were detected in muscle tissue. In contrast, in liver and eWAT we observed increased glucose uptake by 25.6% and 68.6%, respectively, and upregulated expression of glucose transporters with hypothyroidism. To more specifically target bone metabolism and discriminate between the skeletal and systemic effects of hypothyroidism on energy metabolism, male mice were treated with zoledronate (ZOL), a bisphosphonate, that led to decreased bone turnover, trabecular bone gain, and reduced local glucose uptake into bone (−40.4%). However, ZOL-treated mice did not display alterations of systemic glucose handling nor insulin tolerance. Despite the close mutual crosstalk of bone and glucose metabolism, in this study, we show that suppressing bone remodeling does not influence whole-body glucose homeostasis in male mice.

High-fructose feeding suppresses cold-stimulated brown adipose tissue glucose uptake independently of changes in thermogenesis and the gut microbiome

SummaryDiets rich in added sugars are associated with metabolic diseases, and studies have shown a link between these pathologies and changes in the microbiome. Given the reported associations in animal models between the microbiome and brown adipose tissue (BAT) function, and the alterations in the microbiome induced by high-glucose or high-fructose diets, we investigated the potential causal link between high-glucose or -fructose diets and BAT dysfunction in humans. Primary outcomes are changes in BAT cold-induced thermogenesis and the fecal microbiome (clinicaltrials.gov, NCT03188835). We show that BAT glucose uptake, but not thermogenesis, is impaired by a high-fructose but not high-glucose diet, in the absence of changes in the gastrointestinal microbiome. We conclude that decreased BAT glucose metabolism occurs earlier than other pathophysiological abnormalities during fructose overconsumption in humans. This is a potential confounding factor for studies relying on 18F-FDG to assess BAT thermogenesis.

Adipocyte-specific ablation of the Ca2+ pump SERCA2 impairs whole-body metabolic function and reveals the diverse metabolic flexibility of white and brown adipose tissue

ObjectiveSarco/endoplasmic reticulum Ca2+-ATPase (SERCA) transports Ca2+ from the cytosol into the endoplasmic retitculum (ER) and is essential for appropriate regulation of intracellular Ca2+ homeostasis. The objective of this study was to test the hypothesis that SERCA pumps are involved in the regulation of white adipocyte hormone secretion and other aspects of adipose tissue function and that this control is disturbed in obesity-induced type-2 diabetes. MethodsSERCA expression was measured in isolated human and mouse adipocytes as well as in whole mouse adipose tissue by Western blot and RT-qPCR. To test the significance of SERCA2 in adipocyte functionality and whole-body metabolism, we generated adipocyte-specific SERCA2 knockout mice. The mice were metabolically phenotyped by glucose tolerance and tracer studies, histological analyses, measurements of glucose-stimulated insulin release in isolated islets, and gene/protein expression analyses. We also tested the effect of pharmacological SERCA inhibition and genetic SERCA2 ablation in cultured adipocytes. Intracellular and mitochondrial Ca2+ levels were recorded with dual-wavelength ratio imaging and mitochondrial function was assessed by Seahorse technology. ResultsWe demonstrate that SERCA2 is downregulated in white adipocytes from patients with obesity and type-2 diabetes as well as in adipocytes from diet-induced obese mice. SERCA2-ablated adipocytes display disturbed Ca2+ homeostasis associated with upregulated ER stress markers and impaired hormone release. These adipocyte alterations are linked to mild lipodystrophy, reduced adiponectin levels, and impaired glucose tolerance. Interestingly, adipocyte-specific SERCA2 ablation leads to increased glucose uptake in white adipose tissue while the glucose uptake is reduced in brown adipose tissue. This dichotomous effect on glucose uptake is due to differently regulated mitochondrial function. In white adipocytes, SERCA2 deficiency triggers an adaptive increase in fibroblast growth factor 21 (FGF21), increased mitochondrial uncoupling protein 1 (UCP1) levels, and increased oxygen consumption rate (OCR). In contrast, brown SERCA2 null adipocytes display reduced OCR despite increased mitochondrial content and UCP1 levels compared to wild type controls. ConclusionsOur data suggest causal links between reduced white adipocyte SERCA2 levels, deranged adipocyte Ca2+ homeostasis, adipose tissue dysfunction and type-2 diabetes.

Protein Tyrosine Phosphatase 1B Deficiency Improves Glucose Homeostasis in Type 1 Diabetes Treated With Leptin.

Leptin, a hormone secreted by adipocytes, exhibits therapeutic potential for the treatment of type 1 diabetes (T1D). Protein tyrosine phosphatase 1B (PTP1B) is a key enzyme that negatively regulates leptin receptor signaling. Here, the role of PTP1B in the treatment of T1D was investigated using PTP1B-deficient (knockout [KO]) mice and a PTP1B inhibitor. T1D wild-type (WT) mice induced by streptozotocin showed marked hyperglycemia compared with non-T1D WT mice. KO mice displayed significantly improved glucose metabolism equivalent to non-T1D WT mice, whereas peripheral or central administration of leptin partially improved glucose metabolism in T1D WT mice. Peripheral combination therapy of leptin and a PTP1B inhibitor in T1D WT mice improved glucose metabolism to the same level as non-T1D WT mice. Leptin was shown to act on the arcuate nucleus in the hypothalamus to suppress gluconeogenesis in liver and enhance glucose uptake in both brown adipose tissue and soleus muscle through the sympathetic nervous system. These effects were enhanced by PTP1B deficiency. Thus, treatment of T1D with leptin, PTP1B deficiency, or a PTP1B inhibitor was shown to enhance leptin activity in the hypothalamus to improve glucose metabolism. These findings suggest a potential alternative therapy for T1D.

299-OR: Molecular and Physiological Consequences of the Diabetes-Related PGC1A Gly482Ser Polymorphism

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1A) is a nuclear transcriptional coregulator that plays a major role in the control of metabolism and mitochondrial biogenesis. We showed that a diabetes-linked single nucleotide polymorphism (SNP rs8192678) within the coding region of PPARGC1A gene (Gly482Ser) results in decreased protein stability and half-life in liver and beta-cell lines and human induced pluripotent stem cells (iPSCs) . Our mass spectrometry data suggest that degradation of the S482 variant is mediated by phosphorylation at amino acid 482 when a serine is present. A kinome screen identified three potential kinases (NEK2, MARK4 and S6K2) that can modify this site. We found that mutation of the mouse homolog at the conserved site (serine to glycine) similarly stabilized mouse PGC1A. To study the physiological consequences of this SNP, we generated whole-body homozygous glycine (G/G) , serine (S/S) and heterozygous (S/G) mice. We analyzed various metabolic parameters in male (N=10-per genotype) and female (N=8-9) mice subjected to standard chow or high fat, high fructose diet (HFHF) for 14 or 24 weeks. We found that G/G male and female mice had increased caloric intake using metabolic cages without increased body weight. Male mice on a HFHF diet carrying a glycine allele (G/G or S/G) were more resistant to insulin in an insulin tolerance test (ITT) , secreted less insulin in response to a mixed-meal challenge and had decreased glucose uptake in muscle and adipose tissue. In line in humans, non-diabetic subjects with G/G (N=20) or G/S (N=22) variants oxidize more fat while those with S/S variant (N=6) oxidize more carbohydrate over 6-hours following the ingestion of a high-fat meal (68% fat, 18% carbohydrate) . In summary, these results demonstrate that differences in PGC1A stability associated with phosphorylation at site 482 may lead to differences in glucose and fat metabolism, which could explain the link between this SNP and metabolic diseases. Disclosure M.Galipeau: None. M.Faraj: None. M.Oeffinger: None. F.C.Lynn: None. R.A.Screaton: None. T.Alquier: None. J.L.Estall: None. N.Jouvet: None. E.Courty: None. R.Vandenbeek: None. N.P.Khan: None. K.Bouyakdan: None. C.Nian: None. C.Iorio: None. D.D.Scott: None. Funding CIHR (PJT-148771) CIHR (PJT-168853)

824-P: Dual Amylin and Calcitonin Receptor Agonists Improve Insulin Sensitivity and Increase Tissue-Specific Glucose Uptake Independent of Weight Loss

Dual amylin and calcitonin receptor agonists (DACRAs) are known to induce a significant weight loss and improve glucose tolerance and glucose control in rats. However, it is unknown if DACRAs has an insulin sensitizing effect beyond that induced by weight loss and if DACRAs affect tissue specific glucose uptake. Additionally, clamp studies with DACRAs have not previously been performed in diabetic rats. Pre-diabetic ZDSD and diabetic ZDF rats were treated with the DACRA KBP-088 (1.5 nmol//kg, s.c.) for 12 days, and a hyperinsulinemic clamp was conducted on day 13, 24 h post-dosing. In ZDSD rats a hyperinsulinemic euglycemic clamp was carried out, while a hyperinsulinemic isoglycemic clamp was carried out in ZDF rats. In addition, specific glucose uptake was assessed during a hyperinsulinemic isoglycemic clamp in ZDF rats. In ZDSD rats, KBP-088 treatment resulted in a significant reduction in body weight and fasting blood glucose, and improved insulin sensitivity by increasing the glucose infusion rate (GIR) (vehicle: 8.6, KBP-088: 12 mg glucose/kg/min) . In ZDF rats, KBP-088 significantly reduced fasting blood glucose and improved insulin sensitivity (GIR, vehicle: 1.5, KBP-088: 16.5 mg glucose/kg/min) , independent on weight loss. In both studies, KBP-088 increased the rate of glucose clearance, likely be increasing glucose storage, but without altering the endogenous glucose production. Direct assessment of tissue specific glucose uptake showed, that KBP-088 significantly increased glucose uptake in both muscles and adipose tissues when compared to vehicle. In summary, KBP-088 significantly improved insulin sensitivity in both pre-diabetic and diabetic rats and markedly increased tissue specific glucose uptake. Importantly, KBP-088 has an insulin sensitizing effect independent of weight loss, highlighting DACRAs as promising agents for treatment of diabetes. Disclosure A.T.Larsen: Employee; Nordic Bioscience. N.Sonne: None. E.Bredtoft: None. M.A.Karsdal: Employee; Nordic Bioscience A/S, Nordic Bioscience A/S, Nordic Bioscience A/S. K.Henriksen: Employee; Nordic Bioscience A/S, Stock/Shareholder; Nordic Bioscience A/S.

201-LB: Overexpression of GOT1 in Brown Adipose Tissue Enhances Thermogenesis and Glucose Metabolism by Activating the Malate-Aspartate Shuttle

Brown adipose tissue (BAT) is characterized by thermogenic and glucose-consuming properties. BAT takes up large amounts of circulating glucose during cold exposure or pharmacological stimulation of β3-adrenergic receptors (β3AR) , but glucose oxidation in mitochondria only modestly contributes as a fuel source for thermogenesis. How glucose metabolism supports thermogenesis is incompletely understood. Here, we identify a novel role of the malate-aspartate shuttle (MAS) in enhancing thermogenesis, glucose uptake and glycolysis in brown adipose tissue. We found that glutamic-oxaloacetic transaminase 1 (GOT1) , a key enzyme of the MAS, exists at very low levels in BAT but is markedly induced by cold or β3AR agonists, while other MAS enzymes (GOT2 and MDH1/2) remain unchanged. Enforced expression of Got1 in BAT increased energy expenditure in mice and further enhanced thermogenesis upon cold exposure or β3-adrenergic stimulation. Moreover, mice overexpressing Got1 in BAT exhibited enhanced glucose tolerance. Mechanistically, Got1 overexpression stimulated mitochondrial uncoupled respiration. MAS-driven thermogenesis in turn led to AMPK activation, which likely explains enhanced glucose uptake and glycolysis. Collectively, our data demonstrate a novel GOT1-MAS-AMPK axis that regulates thermogenesis and glucose metabolism in cold-activated BAT. Disclosure C. Park: None. H. Cheng: None. S. R. Lee: None. K. Eilertsen: None. J. Chang: None. Funding NIH (DK104748, 1P30GM118430, P30DK072476)

FC028: Characterization of Adipocyte Size and Glucose Uptake in Adipose Tissue with Focus on Different Perirenal Fat Depots

Abstract BACKGROUND AND AIMS Previous studies have suggested that the anatomical location of adipose tissue, and the characteristics of the adipocytes regulating adipose tissue function may be of importance for normal renal function and disease. However, in humans, the adipocyte size and metabolism of the fat depots surrounding the kidney have not been thoroughly characterized. The aim of this study was therefore to characterize adipocyte size and glucose uptake in human perirenal, renal sinus and paranephric adipose tissue. SUBJECTS AND METHODS A total of 25 healthy kidney donors [13 (50%) men, age 48 ± 11 years and BMI 25.7 ± 3.1 kg/m2] were included. Perirenal, renal sinus, paranephric, omental and subcutaneous adipose tissue were collected during laparoscopic unilateral nephrectomy. Adipocyte diameter, basal glucose uptake (no insulin) and insulin-stimulated glucose uptake (25 and 1000 µU/mL) were measured in isolated adipocytes from the different tissues. RESULTS The mean adipocyte cell diameters in the renal fat depots (perirenal, renal sinus and paranephric) were smaller than those in omental and subcutaneous tissue (mean ± sd; 69.3 ± 15.5, 65.5 ± 13.5 and 75.9 ± 16.5 versus 80.3 ± 20.5 and 85.5 ± 16.7 µm, respectively) with adipocytes from the renal sinus fat depot having the smallest cell diameter. Detailed data are displayed in Fig. 1. There were no significant gender differences in cell size and adipocyte size from the different depots did not correlate with body mass index (BMI). Insulin resistance index (HOMA-IR) correlated positively and significantly to adipocyte size in the omental (r = 0.607; P = 0.008), perirenal (r = 0.443; P = 0.027) and paranephric (r = 0.479; P = 0.015) depots. Insulin (both with 25 and 1000 µU/mL) significantly up-regulated glucose uptake in subcutaneous (1.6 and 1.9-fold; P < 0.05), perirenal (1.7 and 2.0-fold; P < 0.01) and paranephric (1.5 and 1.6-folds; P < 0.01) adipocytes, compared with basal (no insulin) as shown in Fig. 2. Interestingly, glucose uptake per cell surface was higher in renal sinus than omental adipocytes (basal (no insulin) 1.2-fold; P < 0.001, physiological (25 µU/mL) and supraphysiological (1000 µU/mL) both 1.3-fold higher; P < 0.001) than omental adipocytes (comparison not shown). CONCLUSION This study in healthy kidney donors indicate differences in different fat depots surrounding the kidney that may be of importance for renal function and disease. The fat depot in the renal sinus, with the smallest adipocytes and potentially a higher glucose uptake, is of specific interest. Detailed metabolic characterization of these fat depots is ongoing. Comparison of adipocyte diameter between the different adipose tissue depots: subcutaneous (n = 24), omental (n = 18), perirenal (n = 25), renal sinus (n = 21) and paranephric adipose tissue (n = 25); Values are mean with SEM as data were normally distributed. **P < 0.01 and ***P < 0.001. Physiological and supraphysiological effect of insulin (25 and 1000 µU/mL) on glucose uptake compared with basal (no insulin) by cell surface in adipocytes isolated from subcutaneous (n = 6), omental (n = 3), perirenal (n = 21), renal sinus (n = 4) and paranephric (n = 18) adipose tissue depots, respectively. Values are median and interquartile range as data were not normally distributed. *P < 0.05, **P < 0.01.

Exercise-induced changes on exerkines that might influence brown adipose tissue metabolism in young sedentary adults

ABSTRACT In rodents, exercise alters the plasma concentration of exerkines that regulate white adipose tissue (WAT) browning or brown adipose tissue (BAT) metabolism. This study aims to analyse the acute and chronic effect of exercise on the circulating concentrations of 16 of these exerkines in humans. Ten young sedentary adults (6 female) performed a maximum walking effort test and a resistance exercise session. The plasma concentration of 16 exerkines was assessed before, and 3, 30, 60, and 120 min after exercise. Those exerkines modified by exercise were additionally measured in another 28 subjects (22 women). We also measured the plasma concentrations of the exerkines before and after a 24-week exercise programme (endurance + resistance; 3-groups: control, moderate-intensity and vigorous-intensity) in 110 subjects (75 women). Endurance exercise acutely increased the plasma concentration of lactate, norepinephrine, brain-derived neurotrophic factor, interleukin 6, and follistatin-like protein 1 (3 min after exercise), and musclin and fibroblast growth factor 21 (30 and 60 min after exercise), decreasing the plasma concentration of leptin (30 min after exercise). Adiponectin, atrial natriuretic peptide (ANP), β-aminoisobutyric acid, meteorin-like, follistatin, pro-ANP, irisin and myostatin were not modified or not detectable. The resistance exercise session increased the plasma concentration of lactate 3 min after exercise. Chronic exercise did not alter the plasma concentration of these exerkines. In sedentary young adults, acute endurance exercise releases to the bloodstream exerkines that regulate BAT metabolism and WAT browning. In contrast, neither a low-volume resistance exercise session nor a 24-week training programme modified plasma levels of these molecules. Highlights Acute endurance exercise increases the plasma concentration of lactate, norepinephrine, brain-derived neurotrophic factor, interleukin 6, follistatin-like protein 1, musclin, and fibroblast growth factor 21, and decrease the plasma concentration of leptin. The exercise-induced change in lactate plasma concentration is positively associated with brown adipose tissue volume, glucose uptake and radiodensity. Neither acute resistance exercise nor chronic exercise significantly alter the plasma concentration of these exerkines. Trial registration: ClinicalTrials.gov identifier: NCT02365129.

Cannabidiol improves glucose utilization and modulates glucose-induced dysmetabolic activities in isolated rats' peripheral adipose tissues

Reduced glucose uptake and utilization, with concomitant lipolysis in adipose tissues has been linked to the pathogenesis of obesity and its complications. The present study investigated the effect of cannabinoid-stimulated glucose uptake on redox imbalance, glucose and lipid metabolisms, as well as cholinergic and purinergic dysfunctions in isolated rats’ adipose tissues. Freshly Isolated rats’ adipose tissues were incubated with glucose and different concentrations of cannabidiol for 2 h at 37 °C. The negative control consisted of incubation without cannabidiol, while normal control consisted of incubations without glucose and/or cannabidiol and Metformin served as the standard drug. Cannabidiol caused an increase in adipose-glucose uptake, with concomitant elevation of glutathione, triglyceride level, superoxide dismutase, catalase and 5′nucleoidase activities. It also caused suppression in malondialdehyde and cholesterol levels, acetylcholinesterase, ENTPDase, fructose-1,6-biphosphatase, glucose 6-phosphatase, glycogen phosphorylase, and lipase activities. In silico studies revealed a strong molecular interaction of cannabidiol with adipose triglyceride lipase, hormone-sensitive lipase, and monoglyceride lipase. These results indicate that cannabidiol-enhanced glucose uptake in adipose tissues is associated with enhanced antioxidative activities, concomitant modulation of cholinergic and purinergic dysfunctions, and improved glucose – lipid homeostasis.