Whole-body Glucose Metabolism Research Articles

Antipsychotics impair regulation of glucose metabolism by central glucose.

Hypothalamic detection of elevated circulating glucose triggers suppression of endogenous glucose production (EGP) to maintain glucose homeostasis. Antipsychotics alleviate symptoms associated with schizophrenia but also increase the risk for impaired glucose metabolism. In the current study, we examined whether two acutely administered antipsychotics from different drug classes, haloperidol (first generation antipsychotic) and olanzapine (second generation antipsychotic), affect the ability of intracerebroventricular (ICV) glucose infusion approximating postprandial levels to suppress EGP. The experimental protocol consisted of a pancreatic euglycemic clamp, followed by kinomic and RNA-seq analyses of hypothalamic samples to determine changes in serine/threonine kinase activity and gene expression, respectively. Both antipsychotics inhibited ICV glucose-mediated increases in glucose infusion rate during the clamp, a measure of whole-body glucose metabolism. Similarly, olanzapine and haloperidol blocked central glucose-induced suppression of EGP. ICV glucose stimulated the vascular endothelial growth factor (VEGF) pathway, phosphatidylinositol 3-kinase (PI3K) pathway, and kinases capable of activating KATP channels in the hypothalamus. These effects were inhibited by both antipsychotics. In conclusion, olanzapine and haloperidol impair central glucose sensing. Although results of hypothalamic analyses in our study do not prove causality, they are novel and provide the basis for a multitude of future studies.

Metformin's Impact on the Microvascular Response to Insulin.

Metformin improves insulin's action on whole-body glucose metabolism in various insulin-resistant populations. The detailed cellular mechanism(s) for its metabolic actions are multiple and still incompletely understood. Beyond metabolic actions, metformin also impacts microvascular function. However, the effects of metformin on microvascular function and microvascular insulin action specifically are poorly defined. In this mini-review, we summarize what is currently known about metformin's beneficial impact on both microvascular function and the microvascular response to insulin while highlighting methodologic issues in the literature that limit straightforward mechanistic understanding of these effects. We examine potential mechanisms for these effects based on pharmacologically dosed studies and propose that metformin may improve human microvascular insulin resistance by attenuating oxidative stress, inflammation, and endothelial dysfunction. Finally, we explore several important evidence gaps and discuss avenues for future investigation that may clarify whether metformin's ability to improve microvascular insulin sensitivity is linked to its positive impact on vascular outcomes.

Biotin, folic acid, and vitamin B12 supplementation given in early lactation to Holstein dairy cows: Their effects on whole-body propionate, glucose, and protein metabolism

Biotin (B8), folic acid (B9), and vitamin B12 (B12) play key roles in energy and protein metabolism. The aim of this study was to evaluate the effects of a B8 supplement, administered alone or combined with B9 and B12 during the transition period on glucose, propionate, and protein metabolism. Thirty-two Holstein multiparous cows were assigned to one of the 4 treatments according to an incomplete block design in a 2 × 2 factorial arrangement: 1) 2-mL of weekly intramuscular injections of saline 9 g/L NaCl (B8 −/B9B12 −); 2) 20 mg/d of dietary B8 (unprotected from ruminal degradation) and 2-mL weekly intramuscular injections of saline 9 g/L NaCl (B8 +/B9B12 −); 3) 2.6 g/d of dietary B9 (unprotected) and 2-mL weekly intramuscular injections of 10 mg of B12 (B8 −/B9B12 +); 4) 20 mg/d of dietary B8, 2.6 g/d of dietary B9 and weekly intramuscular injections of 10 mg of B12 (B8 +/B9B12 +). Treatments were given from − 26–45 days relative to calving date. At 43 (SD:3) days in milk (DIM), D-[6,6-2H2]-glucose (23.9 mmol/h; jugular vein) and [1-13C]-sodium propionate (22.7 mmol/h; ruminal vein) were simultaneously infused for 4 h; the following 2 d, respectively, [13C]-sodium bicarbonate (3.0 mmol/h) and L[1-13C]-Leu (3.7 mmol/h) were infused into a jugular vein for 4 h. Blood samples were collected every 15 min during the last 1.5 h of infusions at 43 DIM and every 20 min at 44 and 45 DIM during the last 2 h of infusions. During the infusion week, there were no treatment effects on milk yield and major milk components, on whole-body propionate (1354 ± 116 mmol/h) and glucose (811 ± 34 mmol/h) rates of appearance, and on the proportion of glucose synthesized from propionate (65.1 ± 4.0%). Nevertheless, plasma glucose concentration during the infusions at 43 DIM for cows receiving the B8 supplement was greater when given in combination with B9 and B12, whereas no effect was noted without B8 supplementation. Whole-body Leu rate of appearance, Leu oxidation, and Leu used for protein synthesis and exportation averaged 133 ± 5, 23 ± 2, 111 ± 4, and 53 ± 2 mmol/h, respectively, and were not different among treatments. The present results might indicate that at the time of infusions between 43 and 45 days in milk under the current conditions, supplies of B8, B9, and B12 were sufficient to meet cow requirements. This reinforces the need to better define under which conditions cows would likely benefit from a supplementation caused by an imbalance between supplies and needs.

198-LB: The Loss of the Lysine Acetyltransferase KAT8 in Adipocytes Confers Lipodystrophy and Metabolic Dysfunction in Male and Female Mice

KAT8, also known as MOF or MYST1, is a lysine acetyltransferase with both histone and non-histone substrates. While KAT8 is the major H4K16 acetyltransferase in Drosophila and mammals and is essential for embryonic development, its role in specific cell types is not well understood. Moreover, studies within the past decade have demonstrated lineage-, differentiation state-, or stress-dependent roles of KAT8. Our recent efforts have shown that KAT8 is necessary for in vitro adipogenesis prior to or during the proliferative phase. Notably, several, independent genetic studies reveal that single nucleotide polymorphisms (SNPs) within or near the KAT8 gene are associated with body mass index and/or waist circumference. To investigate the role of KAT8 in differentiated adipocytes and to understand the contribution of KAT8-deficient adipocytes to whole-body glucose and lipid metabolism, we generated both congenital and doxycycline-inducible adipocyte-specific knockout mice, in which Kat8 gene deletion occurs only in adiponectin-expressing cells. Adult mice lacking adipocyte KAT8 exhibited significant fat mass loss with no change in lean mass. While the size of inguinal and brown adipose tissue was significantly reduced in both sexes fed either chow or high-fat, high-sucrose (HFHS) diet, male mice also had decreased gonadal, retroperitoneal, and mesenteric depots. Histological assessments revealed substantial remodeling within adipose tissue depots, and these mice demonstrated reduced insulin sensitivity and increased lipid accumulation in the liver when fed HFHS diet. Although further investigation is necessary to identify KAT8 targets that confer lipodystrophy, these studies are the first to show the impact of the loss of adipocyte KAT8 in vivo. Disclosure A. J. Richard: n/a. T. M. Mendoza: None. J. M. Stephens: None. Funding National Institutes of Health COBRE P&F grant (P30 GM118430)

Chronic glucocorticoid exposure causes brown adipose tissue whitening, alters whole‐body glucose metabolism and increases tissue uncoupling protein‐1

Adipose tissue (AT) has been found to exist in two predominant forms, white and brown. White adipose tissue (WAT) is the body's conventional storage organ, and brown adipose tissue (BAT) is responsible for non‐shivering thermogenesis which allows mammals to produce heat and regulate body temperature. Studies examining BAT and its role in whole‐body metabolism have found that active BAT utilizes glucose and circulating fatty acids and is associated with improved metabolic outcomes. While the beiging of WAT is a growing area of interest, the possibility of the BAT depot to “whiten” and store more triglycerides also has metabolic and health implications. Currently, there are limited studies that examine the effects of chronic stress and its ability to induce a white‐like phenotype in the BAT depot. This research examined how chronic exposure to the murine stress hormone, corticosterone, for 4 weeks can affect the whitening process of BAT in C57BL/6 male mice. Separate treatments with mirabegron, a known β3‐adrenergic receptor agonist, were used to directly compare the effects of corticosterone with a beiging phenotype. Corticosterone‐treated mice had significantly higher body weight (p ≤ 0.05) and BAT mass (p ≤ 0.05), increased adipocyte area (p ≤ 0.05), were insulin resistant (p ≤ 0.05), and significantly elevated expressions of uncoupling protein 1 (UCP‐1) in BAT (p ≤ 0.05) while mitochondrial content remained unchanged. This whitened phenotype has not been previously associated with increased uncoupling proteins under chronic stress and may represent a compensatory mechanism being initiated under these conditions. These findings have implications for the study of BAT in response to chronic glucocorticoid exposure potentially leading to BAT dysfunction and negative impacts on whole‐body glucose metabolism.

Normal values for 18F-FDG uptake in organs and tissues measured by dynamic whole body multiparametric FDG PET in 126 patients

BackgroundDynamic whole-body (D-WB) FDG PET/CT is a recently developed technique that allows direct reconstruction of multiparametric images of metabolic rate of FDG uptake (MRFDG) and “free” FDG (DVFDG). Multiparametric images have a markedly different appearance than the conventional SUV images obtained by static PET imaging, and normal values of MRFDG and DVFDG in frequently used reference tissues and organs are lacking. The aim of this study was therefore to: (1) provide an overview of normal MRFDG and DVFDG values and range of variation in organs and tissues; (2) analyse organ time-activity curves (TACs); (3) validate the accuracy of directly reconstructed MRFDG tissue values versus manually calculated Ki (and MRFDG) values; and (4) explore correlations between demographics, blood glucose levels and MRFDG values. D-WB data from 126 prospectively recruited patients (100 without diabetes and 26 with diabetes) were retrospectively analysed. Participants were scanned using a 70-min multiparametric PET acquisition protocol on a Siemens Biograph Vision 600 PET/CT scanner. 13 regions (bone, brain grey and white matter, colon, heart, kidney, liver, lung, skeletal muscle of the back and thigh, pancreas, spleen, and stomach) as well as representative pathological findings were manually delineated, and values of static PET (SUV), D-WB PET (Ki, MRFDG and DVFDG) and individual TACs were extracted. Multiparametric values were compared with manual TAC-based calculations of Ki and MRFDG, and correlations with blood glucose, age, weight, BMI, and injected tracer dose were explored.ResultsTissue and organ MRFDG values showed little variation, comparable to corresponding SUV variation. All regional TACs were in line with previously published FDG kinetics, and the multiparametric metrics correlated well with manual TAC-based calculations (r2 = 0.97, p < 0.0001). No correlations were observed between glucose levels and MRFDG in tissues known not to be substrate driven, while tissues with substrate driven glucose uptake had significantly correlated glucose levels and MRFDG values.ConclusionThe multiparametric D-WB PET scan protocol provides normal MRFDG values with little inter-subject variation and in agreement with manual TAC-based calculations and literature values. The technique therefore facilitates both accurate clinical reports and simpler acquisition of quantitative estimates of whole-body tissue glucose metabolism.

Intestinal Epithelial NAD+ Biosynthesis Regulates GLP-1 Production and Postprandial Glucose Metabolism in Mice.

Obesity is associated with perturbations in incretin production and whole-body glucose metabolism, but the precise underlying mechanism remains unclear. Here, we tested the hypothesis that nicotinamide phosphoribosyltransferase (NAMPT), which mediates the biosynthesis of nicotinamide adenine dinucleotide (NAD+), a key regulator of cellular energy metabolism, plays a critical role in obesity-associated intestinal pathophysiology and systemic metabolic complications. To this end, we generated a novel mouse model, namely intestinal epithelial cell-specific Nampt knockout (INKO) mice. INKO mice displayed diminished glucagon-like peptide-1 (GLP-1) production, at least partly contributing to reduced early-phase insulin secretion and postprandial hyperglycemia. Mechanistically, loss of NAMPT attenuated the Wnt signaling pathway, resulting in insufficient GLP-1 production. We also found that diet-induced obese mice had compromised intestinal NAMPT-mediated NAD+ biosynthesis and Wnt signaling pathway, associated with impaired GLP-1 production and whole-body glucose metabolism, resembling the INKO mice. Finally, administration of a key NAD+ intermediate, nicotinamide mononucleotide (NMN), restored intestinal NAD+ levels and obesity-associated metabolic derangements, manifested by a decrease in ileal Proglucagon expression and GLP-1 production as well as postprandial hyperglycemia in INKO and diet-induced obese mice. Collectively, our study provides mechanistic and therapeutic insights into intestinal NAD+ biology related to obesity-associated dysregulation of GLP-1 production and postprandial hyperglycemia.

Impact of Sarcopenia on the Severity of the Liver Damage in Patients With Non-alcoholic Fatty Liver Disease.

An extensive body of the literature shows a strong interrelationship between the pathogenic pathways of non-alcoholic fatty liver disease (NAFLD) and sarcopenia through the muscle-liver-adipose tissue axis. NAFLD is one of the leading causes of chronic liver diseases (CLD) affecting more than one-quarter of the general population worldwide. The disease severity spectrum ranges from simple steatosis to non-alcoholic steatohepatitis (NASH), cirrhosis, and its complications: end-stage chronic liver disease and hepatocellular carcinoma. Sarcopenia, defined as a progressive loss of the skeletal muscle mass, reduces physical performances, is associated with metabolic dysfunction and, possibly, has a causative role in NAFLD pathogenesis. Muscle mass is a key determinant of the whole-body insulin-mediated glucose metabolism and impacts fatty liver oxidation and energy homeostasis. These mechanisms drive the accumulation of ectopic fat both in the liver (steatosis, fatty liver) and in the muscle (myosteatosis). Myosteatosis rather than the muscle mass per se, seems to be closely associated with the severity of the liver injury. Sarcopenic obesity is a recently described entity which associates both sarcopenia and obesity and may trigger worse clinical outcomes including hepatic fibrosis progression and musculoskeletal disabilities. Furthermore, the muscle-liver-adipose tissue axis has a pivotal role in changes of the body composition, resulting in a distinct clinical phenotype that enables the identification of the “sarcopenic NAFLD phenotype.” This review aims to bring some light into the complex relationship between sarcopenia and NAFLD and critically discuss the key mechanisms linking NAFLD to sarcopenia, as well as some of the clinical consequences associated with the coexistence of these two entities: the impact of body composition phenotypes on muscle morphology, the concept of sarcopenic obesity, the relationship between sarcopenia and the severity of the liver damage and finally, the future directions and the existing gaps in the knowledge.

Refeeding activates neurons in the dorsomedial hypothalamus to inhibit food intake and promote positive valence

ObjectiveThe regulation of food intake is a major research area in the study of obesity, which plays a key role in the development of metabolic syndrome. Gene targeting studies have clarified the roles of hypothalamic neurons in feeding behavior, but the deletion of a gene has a long-term effect on neurophysiology. Our understanding of short-term changes such as appetite under physiological conditions is therefore still limited. MethodsTargeted recombination in active populations (TRAP) is a newly developed method for labeling active neurons by using tamoxifen-inducible Cre recombination controlled by the promoter of activity-regulated cytoskeleton-associated protein (Arc/Arg3.1), a member of immediate early genes. Transgenic mice for TRAP were fasted overnight, re-fed with normal diet, and injected with 4-hydroxytamoxifen 1 h after the refeeding to label the active neurons. The role of labeled neurons was examined by expressing excitatory or inhibitory designer receptors exclusively activated by designer drugs (DREADDs). The labeled neurons were extracted and RNA sequencing was performed to identify genes that are specifically expressed in these neurons. ResultsFasting-refeeding activated and labeled neurons in the compact part of the dorsomedial hypothalamus (DMH) that project to the paraventricular hypothalamic nucleus. Chemogenetic activation of the labeled DMH neurons decreased food intake and developed place preference, an indicator of positive valence. Chemogenetic activation or inhibition of these neurons had no influence on the whole-body glucose metabolism. The labeled DMH neurons expressed prodynorphin (pdyn), gastrin-releasing peptide (GRP), cholecystokinin (CCK), and thyrotropin-releasing hormone receptor (Trhr) genes. ConclusionsWe identified a novel cell type of DMH neurons that can inhibit food intake and promote feeding-induced positive valence. Our study provides insight into the role of DMH and its molecular mechanism in the regulation of appetite and emotion.

Dietary palmitate and oleate differently modulate insulin sensitivity in human skeletal muscle

Aims/hypothesisEnergy-dense nutrition generally induces insulin resistance, but dietary composition may differently affect glucose metabolism. This study investigated initial effects of monounsaturated vs saturated lipid meals on basal and insulin-stimulated myocellular glucose metabolism and insulin signalling.MethodsIn a randomised crossover study, 16 lean metabolically healthy volunteers received single meals containing safflower oil (SAF), palm oil (PAL) or vehicle (VCL). Whole-body glucose metabolism was assessed from glucose disposal (Rd) before and during hyperinsulinaemic–euglycaemic clamps with d-[6,6-2H2]glucose. In serial skeletal muscle biopsies, subcellular lipid metabolites and insulin signalling were measured before and after meals.ResultsSAF and PAL raised plasma oleate, but only PAL significantly increased plasma palmitate concentrations. SAF and PAL increased myocellular diacylglycerol and activated protein kinase C (PKC) isoform θ (p < 0.05) but only PAL activated PKCɛ. Moreover, PAL led to increased myocellular ceramides along with stimulated PKCζ translocation (p < 0.05 vs SAF). During clamp, SAF and PAL both decreased insulin-stimulated Rd (p < 0.05 vs VCL), but non-oxidative glucose disposal was lower after PAL compared with SAF (p < 0.05). Muscle serine1101-phosphorylation of IRS-1 was increased upon SAF and PAL consumption (p < 0.05), whereas PAL decreased serine473-phosphorylation of Akt more than SAF (p < 0.05).Conclusions/interpretationLipid-induced myocellular insulin resistance is likely more pronounced with palmitate than with oleate and is associated with PKC isoforms activation and inhibitory insulin signalling.Trial registrationClinicalTrials.gov.NCT01736202.FundingGerman Federal Ministry of Health, Ministry of Culture and Science of the State North Rhine-Westphalia, German Federal Ministry of Education and Research, European Regional Development Fund, German Research Foundation, German Center for Diabetes Research.Graphical abstract

Slow deep breathing modulates cardiac vagal activity but does not affect peripheral glucose metabolism in healthy men

Parasympathetic nervous system innervates peripheral organs including pancreas, hepatic portal system, and gastrointestinal tract. It thereby contributes to the regulation of whole-body glucose metabolism especially in the postprandial state when it promotes secretion of insulin and enhances its action in major target organs. We now aimed to evaluate the effect of parasympathetic modulation on human glucose metabolism. We used slow deep breathing maneuvers to activate the parasympathetic nervous system and tested for effects on metabolism during an oral glucose tolerance test in a randomized, controlled, cross-over trial in 15 healthy young men. We used projections towards the heart as a readout for parasympathetic activity. When analyzing heart rate variability, there was a significant increase of RMSSD (root mean square of successive differences) when participants performed slow deep breathing compared to the control condition, indicating a modulation of parasympathetic activity. However, no statistically significant effects on peripheral glucose metabolism or energy expenditure after the glucose tolerance test were detected. Of note, we detected a significant association between mean heart rate and serum insulin and C-peptide concentrations. While we did not find major effects of slow deep breathing on glucose metabolism, our correlational results suggest a link between the autonomic nervous system and insulin secretion after oral glucose intake. Future studies need to unravel involved mechanisms and develop potential novel treatment approaches for impaired insulin secretion in diabetes.

Metabolomics atlas of oral 13C-glucose tolerance test in mice.

Glucose tolerance represents a complex phenotype in which many tissues play important roles and interact to regulate metabolic homeostasis. Here, we perform an analysis of 13C6-glucose tissue distribution, which maps the metabolome and lipidome across 12 metabolically relevant mouse organs and plasma, with integrated 13C6-glucose-derived carbon tracing during oral glucose tolerance test (OGTT). We measure time profiles of water-soluble metabolites and lipids and integrate the global metabolite response into metabolic pathways. During the OGTT, glucose use is turned on with specific kinetics at the organ level, but fasting substrates like β-hydroxybutyrate are switched off in all organs simultaneously. Timeline profiling of 13C-labeled fatty acids and triacylglycerols across tissues suggests that brown adipose tissue may contribute to the circulating fatty acid pool at maximal plasma glucose levels. The GTTAtlas interactive web application serves as a unique resource for the exploration of whole-body glucose metabolism and time profiles of tissue and plasma metabolites during the OGTT.

Lipid accumulation product (LAP) as a potential index to predict risk of insulin resistance in young, non-obese Asian Indian males from Southern India: observations from hyperinsulinemic-euglycemic clamp studies

IntroductionWe aimed to compare the predictive accuracy of surrogate indices namely the lipid accumulation product (LAP) index, homeostatic model of assessment of insulin resistance (HOMA-IR), fasting glucose-insulin ratio (FG-IR) and...

34-OR: Role of Arid5b in Thermogenesis and Adipose Tissue Browning

Background: Adipose tissue considerably influence metabolic homeostasis and play a central role in regulating whole-body energy and glucose metabolism. Previously, we have reported that mice with the global deletion of Arid5b are lean and have less fat in white and brown adipose tissues. However, this role is unknown in adipocyte specific Arid5b knockout (5bFKO) mice. Aim: We investigated the effects of adipose-specific deficiency of Arid5b on systemic glucose homeostasis and adipose tissue metabolism. Result: Deletion of Arid5b in adipose tissue using adiponectin promoter-driven Cre recombinase significantly improved glucose tolerance with significant reduction of insulin level. Body weight of 5bFKO mice was significantly reduced at the later age. Core body temperature of 5bFKO mice was significantly higher compared to the control mice. Robust increase in the protein expression of uncoupling protein 1 (Ucp1) was observed in inguinal white adipose tissue (iWAT) of 5bFKO mice housed at ambient temperature. This phenotype was further confirmed by prolonged cold exposure where Ucp1 and mitochondrial proteins such as pyruvate dehydrogenase (PDH), mitochondrially encoded cytochrome c oxidase (MTCO1) and ATP5A were substantially increased in iWAT of adipocyte specific Arid5b deficient mice. Gene expression of beige adipogenesis markers such as cell death inducing DFFA like effector A (Cidea) and iodothyronine deiodinase 2 (Dio2) were also significantly increased indicating browning of iWAT. Furthermore, loss of Arid5B in fat led to significant reduction in macrophages and total immune cells in iWAT. All together these results show that the deletion of Arid5b could promote browning of iWAT. Conclusion: These findings demonstrate that Arid5b regulates thermogenic genes expression to promote beige adipocytes formation and controls adipose inflammation. Inhibition of Arid5b may provide a novel therapeutic approach for obesity and diabetes. Disclosure M. Shukare: None. R. Huang: None. A. Ehsani: None. G. Zhang: None. J. Chalise: None. R. H. Whitson: None. K. Itakura: None.

200-LB: Circadian Regulation of the MRTF-SRF Signaling Promotes Beige Adipocyte Development

The adipogenic progenitor transformation into mature adipocytes requires dissolution of intracellular actin cytoskeleton, and the cytoskeleton-MRTF/SRF signaling blocks adipogenesis. The circadian clock confers temporal control in metabolism, with tissue-intrinsic clock circuits contributing to metabolic homeostasis. In the current study, we identify a novel clock-MRTF/SRF regulatory axis that suppresses beige adipogenesis that is required for whole-body glucose metabolism. Key components of the cytoskeleton-MRTF/SRF signaling cascade display circadian oscillations in beige fat depot mediated by Bmal1 transcriptional activity. Genetic loss- or gain-of-functions of Bmal1 in adipogenic precursors markedly altered actin cytoskeleton organization, with silencing of Bmal1 inhibiting F-actin formation and MRTF/SRF activity whereas its forced expression augmenting actin architecture. Furthermore, we show that Bmal1 circadian control of the MRTF/SRF pathway drives beige thermogenic capacity in vivo. Prrx1-Cre-mediated beige fat-selective Bmal1 ablation induced beige depot browning with augmented mitochondrial metabolism, resulting in improved whole-body insulin sensitivity and resistance to obesity. Conversely, beige fat-specific overexpression of Bmal1 suppressed beige thermogenic program leading to impaired glucose tolerance and adipose expansion. Mechanistically, we show that Bmal1 deficiency enhanced beige precursor differentiation and thermogenic induction. Collectively, our findings uncover a temporal regulation of the cytoskeleton-MRTF/SRF signaling that modulates beige thermogenic capacity to maintain metabolic homeostasis. Disclosure X. Xiong: None. R. Liu: None. V. Yechoor: None. P. Saha: None. K. Ma: None. Funding National Institutes of Health (DK112794, DK097160-01); American Heart Association (17GRNT33370012)

FXR Regulates Adipose Tissue Remodeling during Obesity

Obesity is a major epidemic and results in adipose tissue expansion and dysregulated glucose and lipid metabolism. Farnesoid X receptor (FXR) is a nuclear receptor expressed in many tissues that transcriptionally regulates energy homeostasis. However, the role of FXR in adipose tissue remains elusive. We identified Fxr expression in adipocytes isolated from both white (WAT) and brown (BAT) adipose tissues, and uncovered that adipocyte-specific Fxr knockout (Ad-FxrKO) mice recently generated in our laboratory exhibit adipocyte hypertrophy and concomitant reductions in lipolysis and the expression of lipolytic genes in both white and brown fat depots, which is correlated with ectopic fat accumulation in the liver and systemic glucose intolerance when challenged with a 60% high fat diet (HFD) or high fat/high sucrose western diet. Further, transcriptomic analysis of WAT from Ad-FxrKO and control mice upon chow or HFD revealed that many genes enriched in pathways associated with lipid and glucose homeostasis are misregulated in Ad-FxrKO mice with distinct patterns under normal and obese conditions. These data suggest that adipocyte-specific FXR may play a crucial role in regulating fat accumulation and the subsequent glucose homeostasis during diet-induced obesity. In addition to the energy storage and distribution properties of adipose tissue, BAT has high mitochondrial content and burns energy to produce heat and combat obesity. We found that Ad-FxrKO mice display reductions in energy expenditure and the expression of mitochondrial genes, revealing a key role of FXR in controlling BAT mitochondrial function and the consequent thermogenesis. Overall, we demonstrate that FXR can control fat breakdown and regulate mitochondrial functions in the adipose tissue, which in turn, modulates whole-body lipid and glucose metabolism.

Plant-Derived Trans-β-Caryophyllene Boosts Glucose Metabolism and ATP Synthesis in Skeletal Muscle Cells through Cannabinoid Type 2 Receptor Stimulation.

Skeletal muscle plays a pivotal role in whole-body glucose metabolism, accounting for the highest percentage of glucose uptake and utilization in healthy subjects. Impairment of these key functions occurs in several conditions including sedentary lifestyle and aging, driving toward hyperglycemia and metabolic chronic diseases. Therefore, strategies pointed to improve metabolic health by targeting skeletal muscle biochemical pathways are extremely attractive. Among them, we focused on the natural sesquiterpene and cannabinoid type 2 (CB2) receptor agonist Trans-β-caryophyllene (BCP) by analyzing its role in enhancing glucose metabolism in skeletal muscle cells. Experiments were performed on C2C12 myotubes. CB2 receptor membrane localization in myotubes was assessed by immunofluorescence. Within glucose metabolism, we evaluated glucose uptake (by the fluorescent glucose analog 2-NBDG), key enzymes of both glycolytic and oxidative pathways (by spectrophotometric assays and metabolic radiolabeling) and ATP production (by chemiluminescence-based assays). In all experiments, CB2 receptor involvement was tested with the CB2 antagonists AM630 and SR144528. Our results show that in myotubes, BCP significantly enhances glucose uptake, glycolytic and oxidative pathways, and ATP synthesis through a CB2-dependent mechanism. Giving these outcomes, CB2 receptor stimulation by BCP could represent an appealing tool to improve skeletal muscle glucose metabolism, both in physiological and pathological conditions.

Removal of Epididymal Visceral Adipose Tissue Prevents Obesity-Induced Multi-organ Insulin Resistance in Male Mice.

Obesity is associated with insulin resistance, an important risk factor of type 2 diabetes, atherogenic dyslipidemia, and nonalcoholic fatty liver disease. The major purpose of this study was to test hypothesize that prophylactic removal of epididymal visceral adipose tissue (VAT) prevents obesity-induced multi-organ (liver, skeletal muscle, adipose tissue) insulin resistance. Accordingly, we surgically removed epididymal VAT pads from adult C57BL/6J mice and evaluated in vivo and cellular metabolic pathways involved in glucose and lipid metabolism following chronic high-fat diet (HFD) feeding. We found that VAT removal decreases HFD-induced body weight gain while increasing subcutaneous adipose tissue (SAT) mass. Strikingly, VAT removal prevents obesity-induced insulin resistance and hyperinsulinemia and markedly enhances insulin-stimulated AKT-phosphorylation at serine-473 (Ser473) and threonine-308 (Thr308) sites in SAT, liver, and skeletal muscle. VAT removal leads to decreases in plasma lipid concentrations and hepatic triglyceride (TG) content. In addition, VAT removal increases circulating adiponectin, a key insulin-sensitizing adipokine, whereas it decreases circulating interleukin 6, a pro-inflammatory adipokine. Consistent with these findings, VAT removal increases adenosine monophosphate–activated protein kinase C phosphorylation, a major downstream target of adiponectin signaling. Data obtained from RNA sequencing suggest that VAT removal prevents obesity-induced oxidative stress and inflammation in liver and SAT, respectively. Taken together, these findings highlight the metabolic benefits and possible action mechanisms of prophylactic VAT removal on obesity-induced insulin resistance and hepatosteatosis. Our results also provide important insight into understanding the extraordinary capability of adipose tissue to influence whole-body glucose and lipid metabolism as an active endocrine organ.

Central regulation of glucose metabolism in an insulin-dependent and -independent manner.

The central nervous system (CNS) contributes significantly to glucose homeostasis. The available evidence indicates that insulin directly acts on the CNS, in particular the hypothalamus, to regulate hepatic glucose production, thereby controlling whole-body glucose metabolism. Additionally, insulin also acts on the brain to regulate food intake and fat metabolism, which may indirectly regulate glucose metabolism. Studies conducted over the last decade have found that the CNS can regulate glucose metabolism in an insulin-independent manner. Enhancement of central leptin signalling reverses hyperglycaemia in insulin-deficient rodents. Here, I review the mechanisms by which central insulin and leptin actions regulate glucose metabolism. Although clinical studies have shown that insulin treatment is currently indispensable for managing diabetes, unravelling the neuronal mechanisms underlying the central regulation of glucose metabolism will pave the way for the design of novel therapeutic drugs for diabetes.

The mTORC1 complex in pre-osteoblasts regulates whole-body energy metabolism independently of osteocalcin

Overnutrition causes hyperactivation of mTORC1-dependent negative feedback loops leading to the downregulation of insulin signaling and development of insulin resistance. In osteoblasts (OBs), insulin signaling plays a crucial role in the control of systemic glucose homeostasis. We utilized mice with conditional deletion of Rptor to investigate how the loss of mTORC1 function in OB affects glucose metabolism under normal and overnutrition dietary states. Compared to the controls, chow-fed Rptorob−/− mice had substantially less fat mass and exhibited adipocyte hyperplasia. Remarkably, upon feeding with high-fat diet, mice with pre- and post-natal deletion of Rptor in OBs were protected from diet-induced obesity and exhibited improved glucose metabolism with lower fasting glucose and insulin levels, increased glucose tolerance and insulin sensitivity. This leanness and resistance to weight gain was not attributable to changes in food intake, physical activity or lipid absorption but instead was due to increased energy expenditure and greater whole-body substrate flexibility. RNA-seq revealed an increase in glycolysis and skeletal insulin signaling pathways, which correlated with the potentiation of insulin signaling and increased insulin-dependent glucose uptake in Rptor-knockout osteoblasts. Collectively, these findings point to a critical role for the mTORC1 complex in the skeletal regulation of whole-body glucose metabolism and the skeletal development of insulin resistance.