Glucose Uptake In Adipose Tissue Research Articles

Sex Disparities in Thermoregulatory and Metabolic Responses to Mild Cold Exposure Largely Explained by Differences in Body Mass and Body Surface Area

Sex-related differences in thermoregulatory responses to cold exposure, such as differences in metabolic heat production and fuel selection, are often attributed to differences in morphology and body composition. Whether these differences persist in response to cold when comparing lean, healthy men and women with equivalent total body mass (BM, heat producing capacity) and body surface areas (BSA, heat loss capacity) remains unknown. In this study, we aimed to compare thermoregulatory and metabolic responses to cold exposure in both men and women, before and after matching for BM (± 0.6 kg) and BSA (± 0.01 m2). Data included in this study were derived from four previously published studies and an additional 13 men and 23 women who recently completed an identical 3h mild cold exposure protocol. Included in the analyses were 45 healthy men and 23 healthy women [27 years (95% CI: 25 to 28) in men vs. 34 years (95% CI: 30 to 38) in women, P = 0.0003], including 7 men and women of the same age [28 years (95% CI: 22 to 34) vs. 29 years (95% CI: 22 to 37), P = 0.78] matched for BM and BSA. Using a combination of indirect calorimetry, electromyography and positron emission tomography with 11C-acetate and 18F-fluorodeoxyglucose, we quantified mean skin temperature, whole-body energy expenditure (EE), shivering intensity, brown adipose tissue (BAT) oxidative metabolism and glucose uptake. The cold-induced decrease in mean skin temperature was greater in women than men [-6.4°C (95% CI: -6.7 to -6.0) vs. -5.4°C (95% CI: -5.8 to -5.1), P = 0.0004], whereas EE was higher in men compared to women both during room temperature and cold exposure, with the cold-induced increase in EE being slightly greater in men than women [3.8 kJ·min-1 (95% CI: 3.2 to 4.5) vs. 2.8 kJ·min-1 (95% CI: 2.0 to 3.7), P = 0.07]. In contrast, shivering intensity (%MVC) was higher in women compared to men [3.0 %MVC (95% CI: 2.1 to 3.8) vs.1.8 %MVC (95% CI: 1.5 to 2.2), P = 0.0069]. Cold exposure also increased BAT oxidative index to a similar magnitude in men and women, increasing ~4-fold in men and ~3-fold in women (effect of sex, P = 0.2067). Both fractional glucose uptake [0.022 min-1 (95%CI: 0.017 to 0.027) in men and 0.021 min-1 (95%CI: 0.013 to 0.030) in women, P = 0.02] and net glucose uptake in BAT [92 nmol.g-1.min-1 (95%CI: 69 to 115) in men and 91 nmol.g-1.min-1 (95%CI: 53 to 129) in women] were not different between the sexes without or with matching for BM and BSA. The sex differences in mean skin temperature, energy expenditure and shivering intensity were all lost once participants were matched for BM and BSA. The present results suggest that much of the sexual dimorphism in thermoregulatory and metabolic responses to mild cold exposure can be explained by differences in BM and BSA.

Rho Family GTPases and Rho GEFs in Glucose Homeostasis.

Dysregulation of glucose homeostasis leading to metabolic syndrome and type 2 diabetes is the cause of an increasing world health crisis. New intriguing roles have emerged for Rho family GTPases and their Rho guanine nucleotide exchange factor (GEF) activators in the regulation of glucose homeostasis. This review summates the current knowledge, focusing in particular on the roles of Rho GEFs in the processes of glucose-stimulated insulin secretion by pancreatic β cells and insulin-stimulated glucose uptake into skeletal muscle and adipose tissues. We discuss the ten Rho GEFs that are known so far to regulate glucose homeostasis, nine of which are in mammals, and one is in yeast. Among the mammalian Rho GEFs, P-Rex1, Vav2, Vav3, Tiam1, Kalirin and Plekhg4 were shown to mediate the insulin-stimulated translocation of the glucose transporter GLUT4 to the plasma membrane and/or insulin-stimulated glucose uptake in skeletal muscle or adipose tissue. The Rho GEFs P-Rex1, Vav2, Tiam1 and β-PIX were found to control the glucose-stimulated release of insulin by pancreatic β cells. In vivo studies demonstrated the involvement of the Rho GEFs P-Rex2, Vav2, Vav3 and PDZ-RhoGEF in glucose tolerance and/or insulin sensitivity, with deletion of these GEFs either contributing to the development of metabolic syndrome or protecting from it. This research is in its infancy. Considering that over 80 Rho GEFs exist, it is likely that future research will identify more roles for Rho GEFs in glucose homeostasis.

Hibiscus sabdariffa L. calyx extract prevents the adipogenesis of 3T3-L1 adipocytes, and obesity-related insulin resistance in high-fat diet-induced obese rats

Roselle (Hibiscus sabdariffa) is reported to be beneficial in treating obesity which can develop into a range of metabolic disorders. The molecular mechanisms by which roselle extract works to prevent obesity-related insulin resistance remains poorly understood. We hypothesized that the roselle extract can decrease lipid accumulation and improve insulin resistance by downregulating adipogenesis. The aim of this study is to investigate the protective effect of roselle extract on the mechanism of adipogenesis and prevent complications of the obesity-related insulin resistance in high-fat diet-induced obese rats for 8 weeks. Male Sprague Dawley rats were divided into 4 groups: control (C), high-fat diet (HFD), high-fat diet supplemented with 250 mg/kg BW of roselle (R250), and high-fat diet supplemented with 500 mg/kg BW of roselle (R500). The results demonstrated that roselle had the potential to reduce body weight, food intake, lipid profiles, inflammatory cytokines, lipid peroxidation, serum leptin, insulin and duodenal glucose absorption, while significantly increased glucose uptake of adipose tissue and muscle when compared to the HFD group. Roselle can prevent lipid accumulation by suppressing differentiation of 3T3-L1 adipocyte by downregulating the adipogenic gene expression. The results of this study demonstrated that the molecular mechanism underlying the protective effect of roselle, could be an alternative approach for obesity-related insulin resistance prevention.

Visceral adipose tissue glucose uptake is linked to prognosis in multiple myeloma patients: An exploratory study

The use of computerized tomography to opportunistically assess body composition has highlighted abnormalities such as low muscle mass and high adiposity may be hidden conditions in cancer patients. However, the role of skeletal muscle (SM), subcutaneous (SAT) and visceral (VAT) adipose tissue glucose uptake measured by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)-CT on patient prognostication is unclear. Patients with multiple myeloma (MM) with satisfactory image frame for assessing body composition and for semi-quantification of SM, SAT and VAT glucose uptakes were included. Plasmatic pro-inflammatory cytokine and adipokine levels were measured. High VAT mean standardized uptake value (SUV) at baseline was associated with shorter event-free survival (EFS) (hazard ratio [HR]: 7.89; 95% confidence interval [CI], 1.58-39.30; P=0.012) and overall survival (OS) (HR, 15.24; 95% CI, 2.69-86.30; P=0.002) among patients with newly diagnosed MM, even after adjustment for covariates. The highest tertile of VAT SUV was significantly correlated with worse MM-EFS (HR for the highest vs the lowest tertile 3.71; 95% CI, 1.22-10.56; Ptrend=0.035) and mortality (HR, 4.41; 95% CI, 1.28-12.77; Ptrend=0.019). Notably, patients with higher VAT SUV presented with lower VAT area, VAT index, higher SAT SUV, and higher number of individuals with visceral obesity (all P<0.01). Additionally, we found a negative correlation between VAT mean SUV with leptin (R2=0.20, P=0.003); no correlations were detected between VAT mean SUV and resistin, tumor necrosis factor (TNF) or interleukin (IL)-6. Functional VAT activity estimated by 18F-FDG PET-CT is a relevant prognostic factor in MM patients, specifically, a higher VAT SUV might be an early biomarker of cancer cachexia in these patients.

STEROID-INDUCED GLUCOSE INTOLERANCE IN CHILDREN WITH NEPHROTIC SYNDROME AND SYSTEMIC LUPUS ERYTHEMATOUS

Steroids are the cornerstone in treatment of idiopathic nephrotic syndrome (INS) and systemic lupus erythematosus (SLE). Steroids are used for their anti-inflammatory and immunosuppressive effects. Although, they are known to cause serious adverse effects including glucose intolerance.The mechanisms by which steroid-induced glucose intolerance (SIGI) include: increased gluconeogenesis in the liver, reduced glucose uptake in adipose tissue and skeletal muscle, and induced pancreatic β-cell dysfunction. The exact prevalence of SIGI in patients on chronic steroid therapy is unknown. The prevalence was reported to vary between 0% and 65% and several risk factors for the developing SIGI have been identified. THE AIM OF THIS WORK The aim of this work was to study steroid-induced glucose intolerance in patients with idiopathic nephrotic syndrome and systemic lupus erythematosus on long term steroid treatment and to determine the risk factors associated with development of steroid-induced glucose intolerance.SUBJECTSSubjects were recruited directly from outpatient Pediatric Nephrology Clinic. Sixty children aged from 2 to 18 years were enrolled; including 2 groups: thirty patients with INS and thirty patients with SLE on long-term steroids use for at least 6 months.

Mechanisms by which adiponectin reverses high fat diet-induced insulin resistance in mice

Adiponectin has emerged as a potential therapy for type 2 diabetes mellitus, but the molecular mechanism by which adiponectin reverses insulin resistance remains unclear. Two weeks of globular adiponectin (gAcrp30) treatment reduced fasting plasma glucose, triglyceride (TAG), and insulin concentrations and reversed whole-body insulin resistance, which could be attributed to both improved insulin-mediated suppression of endogenous glucose production and increased insulin-stimulated glucose uptake in muscle and adipose tissues. These improvements in liver and muscle sensitivity were associated with ∼50% reductions in liver and muscle TAG and plasma membrane (PM)-associated diacylglycerol (DAG) content and occurred independent of reductions in total ceramide content. Reductions of PM DAG content in liver and skeletal muscle were associated with reduced PKCε translocation in liver and reduced PKCθ and PKCε translocation in skeletal muscle resulting in increased insulin-stimulated insulin receptor tyrosine1162 phosphorylation, IRS-1/IRS-2-associated PI3-kinase activity, and Akt-serine phosphorylation. Both gAcrp30 and full-length adiponectin (Acrp30) treatment increased eNOS/AMPK activation in muscle and muscle fatty acid oxidation. gAcrp30 and Acrp30 infusions also increased TAG uptake in epididymal white adipose tissue (eWAT), which could be attributed to increased lipoprotein lipase (LPL) activity. These data suggest that adiponectin and adiponectin-related molecules reverse lipid-induced liver and muscle insulin resistance by reducing ectopic lipid storage in these organs, resulting in decreased plasma membrane sn-1,2-DAG-induced nPKC activity and increased insulin signaling. Adiponectin mediates these effects by both promoting the storage of TAG in eWAT likely through stimulation of LPL as well as by stimulation of AMPK in muscle resulting in increased muscle fat oxidation.

Characterization of viral insulins reveals white adipose tissue-specific effects in mice

ObjectiveMembers of the insulin/insulin-like growth factor (IGF) superfamily are well conserved across the evolutionary tree. We recently showed that four viruses in the Iridoviridae family possess genes that encode proteins highly homologous to human insulin/IGF-1. Using chemically synthesized single-chain (sc), i.e., IGF-1-like, forms of the viral insulin/IGF-1-like peptides (VILPs), we previously showed that they can stimulate human receptors. Because these peptides possess potential cleavage sites to form double chain (dc), i.e., more insulin-like, VILPs, in this study, we have characterized dc forms of VILPs for Grouper iridovirus (GIV), Singapore grouper iridovirus (SGIV) and Lymphocystis disease virus-1 (LCDV-1) for the first time. MethodsThe dcVILPs were chemically synthesized. Using murine fibroblast cell lines overexpressing insulin receptor (IR-A or IR-B) or IGF1R, we first determined the binding affinity of dcVILPs to the receptors and characterized post-receptor signaling. Further, we used C57BL/6J mice to study the effect of dcVILPs on lowering blood glucose. We designed a 3-h dcVILP in vivo infusion experiment to determine the glucose uptake in different tissues. ResultsGIV and SGIV dcVILPs bind to both isoforms of human insulin receptor (IR-A and IR-B) and to the IGF1R, and for the latter, show higher affinity than human insulin. These dcVILPs stimulate IR and IGF1R phosphorylation and post-receptor signaling in vitro and in vivo. Both GIV and SGIV dcVILPs stimulate glucose uptake in mice. In vivo infusion experiments revealed that while insulin (0.015 nmol/kg/min) and GIV dcVILP (0.75 nmol/kg/min) stimulated a comparable glucose uptake in heart and skeletal muscle and brown adipose tissue, GIV dcVILP stimulated 2-fold higher glucose uptake in white adipose tissue (WAT) compared to insulin. This was associated with increased Akt phosphorylation and glucose transporter type 4 (GLUT4) gene expression compared to insulin in WAT. ConclusionsOur results show that GIV and SGIV dcVILPs are active members of the insulin superfamily with unique characteristics. Elucidating the mechanism of tissue specificity for GIV dcVILP will help us to better understand insulin action, design new analogs that specifically target the tissues and provide new insights into their potential role in disease.

Diets enriched with coconut, fish, or olive oil modify peripheral metabolic effects of ozone in rats

Dietary factors may modulate metabolic effects of air pollutant exposures. We hypothesized that diets enriched with coconut oil (CO), fish oil (FO), or olive oil (OO) would alter ozone-induced metabolic responses. Male Wistar-Kyoto rats (1-month-old) were fed normal diet (ND), or CO-, FO-, or OO-enriched diets. After eight weeks, animals were exposed to air or 0.8 ppm ozone, 4 h/day for 2 days. Relative to ND, CO- and OO-enriched diet increased body fat, serum triglycerides, cholesterols, and leptin, while all supplements increased liver lipid staining (OO > FO > CO). FO increased n-3, OO increased n-6/n-9, and all supplements increased saturated fatty-acids. Ozone increased total cholesterol, low-density lipoprotein, branched-chain amino acids (BCAA), induced hyperglycemia, glucose intolerance, and changed gene expression involved in energy metabolism in adipose and muscle tissue in rats fed ND. Ozone-induced glucose intolerance was exacerbated by OO-enriched diet. Ozone increased leptin in CO- and FO-enriched groups; however, BCAA increases were blunted by FO and OO. Ozone-induced inhibition of liver cholesterol biosynthesis genes in ND-fed rats was not evident in enriched dietary groups; however, genes involved in energy metabolism and glucose transport were increased in rats fed FO and OO-enriched diet. FO- and OO-enriched diets blunted ozone-induced inhibition of genes involved in adipose tissue glucose uptake and cholesterol synthesis, but exacerbated genes involved in adipose lipolysis. Ozone-induced decreases in muscle energy metabolism genes were similar in all dietary groups. In conclusion, CO-, FO-, and OO-enriched diets modified ozone-induced metabolic changes in a diet-specific manner, which could contribute to altered peripheral energy homeostasis.

Skeletal glucocorticoid signalling determines leptin resistance and obesity in aging mice

ObjectiveAging and chronic glucocorticoid excess share a number of critical features, including the development of central obesity, insulin resistance and osteoporosis. Previous studies have shown that skeletal glucocorticoid signalling increases with aging and that osteoblasts mediate the detrimental skeletal and metabolic effects of chronic glucocorticoid excess. Here, we investigated whether endogenous glucocorticoid action in the skeleton contributes to metabolic dysfunction during normal aging. MethodsMice lacking glucocorticoid signalling in osteoblasts and osteocytes (HSD2OB/OCY-tg mice) and their wild-type littermates were studied until 3, 6, 12 and 18 months of age. Body composition, adipose tissue morphology, skeletal gene expression and glucose/insulin tolerance were assessed at each timepoint. Leptin sensitivity was assessed by arcuate nucleus STAT3 phosphorylation and inhibition of feeding following leptin administration. Tissue-specific glucose uptake and adipose tissue oxygen consumption rate were also measured. ResultsAs they aged, wild-type mice became obese and insulin-resistant. In contrast, HSD2OB/OCY-tg mice remained lean and insulin-sensitive during aging. Obesity in wild-type mice was due to leptin resistance, evidenced by an impaired ability of exogenous leptin to suppress food intake and phosphorylate hypothalamic STAT3, from 6 months of age onwards. In contrast, HSD2OB/OCY-tg mice remained leptin-sensitive throughout the study. Compared to HSD2OB/OCY-tg mice, leptin-resistant wild-type mice displayed attenuated sympathetic outflow, with reduced tyrosine hydroxylase expression in both the hypothalamus and thermogenic adipose tissues. Adipose tissue oxygen consumption rate declined progressively in aging wild-type mice but was maintained in HSD2OB/OCY-tg mice. At 18 months of age, adipose tissue glucose uptake was increased 3.7-fold in HSD2OB/OCY-tg mice, compared to wild-type mice. ConclusionsSkeletal glucocorticoid signalling is critical for the development of leptin resistance, obesity and insulin resistance during aging. These findings underscore the skeleton's importance in the regulation of body weight and implicate osteoblastic/osteocytic glucocorticoid signalling in the aetiology of aging-related obesity and metabolic disease.

SIRT1 deacetylates mitochondrial trifunctional enzyme \u03b1 subunit to inhibit ubiquitylation and decrease insulin resistance

Dysregulation of free acid metabolism is a major contributor to the development of insulin resistance and diabetes. Mitochondrial trifunctional enzyme subunit (MTPα) has a critical role in fatty acid β-oxidation. However, the association between MTPα and insulin resistance is not definitively known. Here, we aimed to determine how MTPα affects insulin resistance. We tested how MTPα affected glucose uptake in insulin-resistant 3T3-L1 adipocytes and white adipose tissue (WAT) of db/db diabetic mice. We also measured how acetylation and ubiquitylation modifications regulated MTPα activation and stability, using quantitative real-time polymerase chain reactions, immunoblotting, and immunoprecipitation. We found that MTPα overexpression promoted glucose uptake via Glut4 translocation to the plasma membrane in 3T3-L1 adipocytes. Moreover, MTPα upregulation decreased glycemia in db/db mice. Deacetylation increased MTPα protein stability and its ability to reduce insulin resistance. The activation of SIRT1, a major deacetylase, prevented MTPα degradation by decreasing its acetylation in adipocytes. Our study demonstrates a new role for MTPα in reducing insulin resistance. Acetylation and ubiquitylation modifications of MTPα were crucial to regulating its function in glucose metabolism.

LNK deficiency decreases obesity-induced insulin resistance by regulating GLUT4 through the PI3K-Akt-AS160 pathway in adipose tissue.

In recent years, LNK, an adapter protein, has been found to be associated with metabolic diseases, including hypertension and diabetes. We found that the expression of LNK in human adipose tissue was positively correlated with serum glucose and insulin in obese people. We examined the role of LNK in insulin resistance and systemic energy metabolism using LNK-deficient mice (LNK-/-). With consumption of a high-fat diet, wild type (WT) mice accumulated more intrahepatic triglyceride, higher serum triglyceride (TG), free fatty acid (FFA) and high sensitivity C-reactive protein (hsCRP) compared with LNK-/- mice. However, there was no significant difference between LNK-/- and WT mice under normal chow diet. Meanwhile, glucose transporter 4 (GLUT4) expression in adipose tissue and insulin-stimulated glucose uptake in adipocytes were increased in LNK-/- mice. LNK-/- adipose tissue showed activated reactivity for IRS1/PI3K/Akt/AS160 signaling, and administration of a PI3K inhibitor impaired glucose uptake. In conclusion, LNK plays a pivotal role in adipose glucose transport by regulating insulin-mediated IRS1/PI3K/Akt/AS160 signaling.

The Precious Few Grams of Glucose During Exercise.

As exercise intensity exceeds 65% of maximal oxygen uptake carbohydrate energy sources predominate. However, relative to the meager 4–5 g blood glucose pool size in a postabsorptive individual (0.9–1.0 g·L−1 × 5 L blood = 18–20 kcal), carbohydrate (CHO) oxidation rates of 20 kcal·min−1 can be sustained in a healthy and fit person for one hour, if not longer, all the while euglycemia is maintained. While glucose rate of appearance (i.e., production, Ra) from splanchnic sources in a postabsorptive person can rise 2–3 fold during exercise, working muscle and adipose tissue glucose uptake must be restricted while other energy substrates such as glycogen, lactate, and fatty acids are mobilized and utilized. If not for the use of alternative energy substrates hypoglycemia would occur in less than a minute during hard exercise because blood glucose disposal rate (Rd) could easily exceed glucose production (Ra) from hepatic glycogenolysis and gluconeogenesis. The goal of this paper is to present and discuss the integration of physiological, neuroendocrine, circulatory, and biochemical mechanisms necessary for maintenance of euglycemia during sustained hard physical exercise.

Exercise training improves adipose tissue metabolism and vasculature regardless of baseline glucose tolerance and sex

IntroductionWe investigated the effects of a supervised progressive sprint interval training (SIT) and moderate-intensity continuous training (MICT) on adipocyte morphology and adipose tissue metabolism and function; we also tested whether...

Science, Medicine, and the Anesthesiologist

Science, Medicine, and the Anesthesiologist

Loss of Uncoupling Protein 3 Attenuates Western Diet-Induced Obesity, Systemic Inflammation, and Insulin Resistance in Rats.

Uncoupling protein 3 (UCP3) is a mitochondrial carrier related to fatty acid metabolism. Although gene variants of UCP3 are associated with human obesity, their contribution to increased adiposity remains unclear. This study investigated the impact that loss of UCP3 has on diet-induced obesity in rats. Male UCP3 knockout rats (ucp3-/- ) and wild-type littermates (ucp3+/+ ) were fed a high-fat, high-carbohydrate Western diet for 21 weeks. Body composition was analyzed by EchoMRI. Whole-body insulin sensitivity and rates of tissue glucose uptake were determined by using hyperinsulinemic-euglycemic clamp. Changes in tissue physiology were interrogated by microscopy and RNA sequencing. Loss of UCP3 decreased fat mass gain, white adipocytes size, and systemic inflammation. The ucp3-/- rats also exhibited preserved insulin sensitivity and increased glucose uptake in interscapular brown adipose tissue (iBAT). Brown adipocytes from ucp3-/- rats were protected from cellular degeneration caused by lipid accumulation and from reactive oxygen species-induced protein sulfonation. Increased glutathione levels in iBAT from ucp3-/- rats were linked to upregulation of genes encoding enzymes from the transsulfuration pathway in that tissue. Loss of UCP3 partially protects rats from diet-induced obesity. This phenotype is related to induction of a compensatory antioxidant mechanism and prevention of iBAT whitening.

Insulin sensitivity in long-lived growth hormone-releasing hormone knockout mice.

Our previous studies showed that loss-of-function mutation of growth hormone releasing hormone (GHRH) results in increased longevity and enhanced insulin sensitivity in mice. However, the details of improved insulin action and tissue-specific insulin signaling are largely unknown in this healthy-aging mouse model. We conducted hyperinsulinemic-euglycemic clamp to investigate mechanisms underlying enhanced insulin sensitivity in growth hormone (GH) deficient mice. Further, we assessed in vivo tissue-specific insulin activity via activation of PI3K-AKT and MAPK-ERK1/2 cascades using western blot. Clamp results showed that the glucose infusion rate required for maintaining euglycemia was much higher in GHRH-/- mice compared to WT controls. Insulin-mediated glucose production was largely suppressed, whereas glucose uptake in skeletal muscle and brown adipose tissue were significant enhanced in GHRH-/- mice compared to WT controls. Enhanced capacity of insulin-induced activation of the PI3K-AKT and MAPK-ERK1/2 signaling were observed in a tissue-specific manner in GHRH-/- mice. Enhanced systemic insulin sensitivity in long-lived GHRH-/- mice is associated with differential activation of insulin signaling cascades among various organs. Improved action of insulin in the insulin sensitive tissues is likely to mediate the prolonged longevity and healthy-aging effects of GH deficiency in mice.

Effects of High-Intensity Exercise Training on Adipose Tissue Mass, Glucose Uptake and Protein Content in Pre- and Post-menopausal Women.

The menopausal transition is accompanied by changes in adipose tissue storage, leading to an android body composition associated with increased risk of type 2 diabetes and cardiovascular disease in post-menopausal women. Estrogens probably affect local adipose tissue depots differently. We investigated how menopausal status and exercise training influence adipose tissue mass, adipose tissue insulin sensitivity and adipose tissue proteins associated with lipogenesis/lipolysis and mitochondrial function. Healthy, normal-weight pre- (n = 21) and post-menopausal (n = 20) women participated in high-intensity exercise training three times per week for 12 weeks. Adipose tissue distribution was determined by dual-energy x-ray absorptiometry and magnetic resonance imaging. Adipose tissue glucose uptake was assessed by positron emission tomography/computed tomography (PET/CT) by the glucose analog [18F]fluorodeoxyglucose ([18F]FDG) during continuous insulin infusion (40 mU·m−2·min−1). Protein content associated with insulin signaling, lipogenesis/lipolysis, and mitochondrial function were determined by western blotting in abdominal and femoral white adipose tissue biopsies. The mean age difference between the pre- and the post-menopausal women was 4.5 years. Exercise training reduced subcutaneous (~4%) and visceral (~6%) adipose tissue masses similarly in pre- and post-menopausal women. Insulin-stimulated glucose uptake, assessed by [18F]FDG-uptake during PET/CT, was similar in pre- and post-menopausal women in abdominal, gluteal, and femoral adipose tissue depots, despite skeletal muscle insulin resistance in post- compared to pre-menopausal women in the same cohort. Insulin-stimulated glucose uptake in adipose tissue depots was not changed after 3 months of high-intensity exercise training, but insulin sensitivity was higher in visceral compared to subcutaneous adipose tissue depots (~139%). Post-menopausal women exhibited increased hexokinase and adipose triglyceride lipase content in subcutaneous abdominal adipose tissue. Physical activity in the early post-menopausal years reduces abdominal obesity, but insulin sensitivity of adipose tissue seems unaffected by both menopausal status and physical activity.

Abscisic Acid: A Conserved Hormone in Plants and Humans and a Promising Aid to Combat Prediabetes and the Metabolic Syndrome.

Abscisic acid (ABA) is a hormone with a very long evolutionary history, dating back to the earliest living organisms, of which modern (ABA-producing) cyanobacteria are likely the descendants, well before separation of the plant and animal kingdoms, with a conserved role as a signal regulating cell responses to environmental challenges. In mammals, nanomolar ABA controls the metabolic response to glucose availability by stimulating glucose uptake in skeletal muscle and adipose tissue with an insulin-independent mechanism and increasing energy expenditure in the brown and white adipose tissues. Activation by ABA of AMP-dependent kinase (AMPK), in contrast to the insulin-induced activation of AMPK-inhibiting Akt, is responsible for stimulation of GLUT4-mediated muscle glucose uptake, and for the browning effect on white adipocytes. Intake of micrograms per Kg body weight of ABA improves glucose tolerance in both normal and in borderline subjects and chronic intake of such a dose of ABA improves blood glucose, lipids and morphometric parameters (waist circumference and body mass index) in borderline subjects for prediabetes and the metabolic syndrome. This review summarizes the most recent results obtained in vivo with microgram amounts of ABA, the role of the receptor LANCL2 in the hormone’s action and the significance of the endowment by mammals of two different hormones controlling the metabolic response to glucose availability. Finally, open issues in need of further investigation and perspectives for the clinical use of nutraceutical ABA are discussed.

1822-P: Regulation of Trafficking of Lipids from Liver to Fat by ApoA4 in a Mouse Model of Nonalcoholic Steatohepatitis

Lipogenesis and lipolysis largely determining adipose tissues and liver lipid content, and the imbalance between them contributes to fatty liver disease and metabolic syndromes. Lipogenesis and lipolysis are regulated by nutritional signals and metabolic hormones such as insulin through multiple mechanisms. Apolipoprotein A-IV (ApoA4), secreted largely by intestine, is existed as the composition of HDL and as the free form mostly in blood. ApoA4 plays the important roles in anti-atherosclerosis and lowering blood glucose. After we found its suppressing hepatic gluconeogenesis via NR1D1/NR4A1, and promoting glucose uptake in adipose tissues through PI3K-Akt-GLUT4, we have studied the action of ApoA4 on lipid metabolism with ApoA4 knock-out mice (A4KO). We found that ApoA4 deficiency resulted in worse fatty liver in diet induced obesity (DIO) mice. ApoA4 deficiency lowered the expression of hepatic ATGL, the rate-limiting enzyme for lipolysis, but enhanced the expression of key lipogenic enzymes such as ACC and SCD1. However, the expression of ATGL was increased and the expression of ACC, SCD1, FAS as well as their transcriptional activator SREBP1 were decreased from both BAT and WAT in A4KO mice. Furthermore, ApoA4 deletion also resulted in the inhibited expression of key proteins in thermogenesis pathway SIRT1, PGC1 and UCP1. Moreover, either overexpression of ApoA4 by delivery of AAV-ApoA4 or one time injection of ApoA4 protein resulted in reversed expression of key enzymes for lipogenesis and lipolysis both in liver and adipose tissues from A4KO DIO mice. These data suggest that ApoA4 may promote lipolysis in liver, but inhibited lipolysis and enhance lipogenesis and energy metabolism in adipose tissues, implying ApoA4’s action of regulating the trafficking of lipids from liver to fat and then turn fat into energy for burning. Disclosure X. Li: None. X. Liu: None. C. Cheng: None. J. Zhou: None. J. Fan: None. S. Li: None. Funding National Natural Science Foundation of China (81770798, 81700691)

695-P: Grand-Maternal Exercise Improves Glucose Tolerance in Second Generation Offspring

Maternal obesity and diet are critical risk factors for development of obesity and diabetes in both first (F1) and second (F2) generation offspring. Maternal exercise in mice improves F1 metabolic health and prevents the detrimental effects of maternal high-fat-diet (HFD) on F1 offspring. Whether the beneficial effects of maternal exercise can be transmitted to the F2 generation is unknown. Here, C57BL/6 females were fed a chow or HFD and subdivided into cages with (Exercise) or without (Sedentary) running wheels for 2wks before breeding and during ∼3wks gestation. Male F1 offspring were sedentary and chow-fed, and at 8 wks of age were bred with age-matched females from untreated parents. F2 offspring were studied based on grand-maternal treatment: chow sedentary; chow trained; HFD sedentary; HFD trained (n= ∼10 litters/group; 348 total mice). F2 offspring were sedentary and chow-fed and studied up to 52 wks of age. For F2 males, grand-maternal exercise significantly improved glucose tolerance at 24, 36 and 52 wks and decreased insulin concentrations at 52 wks. Grand-maternal exercise also resulted in F2 males with lower body weights, decreased fat mass and increased lean mass at 52wks. Grand-maternal HFD decreased glucose uptake in skeletal muscles and adipose tissue in F2 males, but there was no effect of grand-maternal exercise, suggesting that the mechanism for improved glucose tolerance in F2 males does not involve glucose uptake in these tissues. For female F2, grand-maternal exercise had no effect on insulin concentrations, body weights or tissue glucose uptake. However, grand-maternal exercise significantly improved glucose tolerance in female F2 at 36 and 52 wks, and decreased fat mass and increased lean mass. Maternal exercise has beneficial effects on the metabolic health of adult F2 male and female offspring. These novel findings suggest that maternal exercise can prevent obesity and diabetes in multiple generations and may help reduce the incidence of these diseases worldwide. Disclosure A.B.A. Wagner: None. J. Kusuyama: None. P. Nigro: None. N.S. Makarewicz: None. M.F. Hirshman: Stock/Shareholder; Self; Abbott Laboratories, AbbVie Inc., Amgen, Colgate-Palmolive, Eli Lilly and Company, Medtronic. L.J. Goodyear: None. Funding American Diabetes Association (1-17-PMF-009 to A.B.A.W.); National Institutes of Health (R01DK101043)