Control of lipolysis by a population of oxytocinergic sympathetic neurons.

Oxytocin (OXT), a nine-amino-acid peptide produced in the hypothalamus and released by the posterior pituitary, has well-known actions in parturition, lactation and social behaviour1, and has become an intriguing therapeutic target for conditions such as autism and schizophrenia2. Exogenous OXT has also been shown to have effects on body weight, lipid levels and glucose homeostasis1,3, suggesting that it may also have therapeutic potential for metabolic disease1,4. It is unclear, however, whether endogenous OXT participates in metabolic homeostasis. Here we show that OXT is a critical regulator of adipose tissue lipolysis in both mice and humans. In addition, OXT serves to facilitate the ability of ß-adrenergic agonists to fully promote lipolysis. Most surprisingly, the relevant source of OXT in these metabolic actions is a previously unidentified subpopulation of tyrosine hydroxylase-positive sympathetic neurons. Our data reveal that OXT from the peripheral nervous system is an endogenous regulator of adipose and systemic metabolism.

Associations Among Adipose Tissue Immunology, Inflammation, Exosomes and Insulin Sensitivity in People With Obesity and Nonalcoholic Fatty Liver Disease.

BACKGROUND AND AIMS: Insulin resistance is a key factor in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). We evaluated the importance of subcutaneous abdominal adipose tissue (SAAT) inflammation and both plasma and SAAT-derived exosomes in regulating insulin sensitivity in people with obesity and NAFLD. METHODS: Adipose tissue inflammation (macrophage and T-cell content and expression of proinflammatory cytokines), liver and whole-body insulin sensitivity (assessed using a hyperinsulinemic-euglycemic clamp and glucose tracer infusion), and 24-hour serial plasma cytokine concentrations were evaluated in 3 groups stratified by adiposity and intrahepatic triglyceride (IHTG) content: (1) lean with normal IHTG content (LEAN; N = 14); (2) obese with normal IHTG content (OB-NL; N = 28); and (3) obese with NAFLD (OB-NAFLD; N = 28). The effect of plasma and SAAT-derived exosomes on insulin-stimulated Akt phosphorylation in human skeletal muscle myotubes and mouse primary hepatocytes was assessed in a subset of participants. RESULTS: Proinflammatory macrophages, proinflammatory CD4 and CD8 T-cell populations, and gene expression of several cytokines in SAAT were greater in the OB-NAFLD than the OB-NL and LEAN groups. However, with the exception of PAI-1, which was greater in the OB-NAFLD than the LEAN and OB-NL groups, 24-hour plasma cytokine concentration areas-under-the-curve were not different between groups. The percentage of proinflammatory macrophages and plasma PAI-1 concentration areas-under-the-curve were inversely correlated with both hepatic and whole-body insulin sensitivity. Compared with exosomes from OB-NL participants, plasma and SAAT-derived exosomes from the OB-NAFLD group decreased insulin signaling in myotubes and hepatocytes. CONCLUSIONS: Systemic insulin resistance in people with obesity and NAFLD is associated with increased plasma PAI-1 concentrations and both plasma and SAAT-derived exosomes. ClinicalTrials.gov number: NCT02706262 (https://clinicaltrials.gov/ct2/show/NCT02706262).

Do lifestyle factors and quality of life differ in people with metabolically healthy and unhealthy obesity?

BACKGROUND AND OBJECTIVES: Although obesity is typically associated with metabolic co-morbidities, some people with obesity do not develop metabolic abnormalities. We evaluated whether modifiable lifestyle factors (i.e., physical activity, dietary composition, and sleep characteristics) can help explain why some people with obesity are metabolically healthy (MHO) and whether metabolically unhealthy obesity (MUO) affects quality of life (QOL). SUBJECTS/METHODS: Physical activity and sleep characteristics were assessed by using tri-axial accelerometers and dietary intake, sleep quality, and QOL were evaluated by using validated questionnaires in people stratified into three groups: (1) lean with normal glucose tolerance, plasma triglyceride (TG) concentration and intrahepatic TG (IHTG) content (metabolically healthy lean [MHL]; n = 20); (2) obesity and normal glucose tolerance, plasma TG concentration and IHTG content (MHO; n = 36); and (3) obesity with abnormal glucose metabolism and hepatic steatosis (MUO; n = 43). RESULTS: People with MHO performed ~45-min more light-intensity physical activity/day than the MHL and MUO groups (P < 0.05). QOL, particularly the physical function domain, was higher in the MHO than the MUO group (P < 0.05). Although self-reported intake of starch, dairy, and cured meats were higher in the MUO than the MHO group (P < 0.02), the absolute differences were small and unlikely to have metabolic effects. No differences were found in sleep duration or quality between groups. CONCLUSIONS: These data suggest physical activity, but not sleep or dietary intake, contribute to better metabolic health in people with MHO than those with MUO, and that QOL is lower in people with MUO than those with MHO.

Increased Adipose Tissue Fibrogenesis, Not Impaired Expandability, Is Associated With Nonalcoholic Fatty Liver Disease.

BACKGROUND AND AIMS: It is proposed that impaired expansion of subcutaneous adipose tissue (SAT) and an increase in adipose tissue (AT) fibrosis causes ectopic lipid accumulation, insulin resistance (IR), and metabolically unhealthy obesity. We therefore evaluated whether a decrease in SAT expandability, assessed by measuring SAT lipogenesis (triglyceride [TG] production), and an increase in SAT fibrogenesis (collagen production) are associated with NAFLD and IR in persons with obesity. APPROACH AND RESULTS: In vivo abdominal SAT lipogenesis and fibrogenesis, expression of SAT genes involved in extracellular matrix (ECM) formation, and insulin sensitivity were assessed in three groups of participants stratified by adiposity and intrahepatic TG (IHTG) content: (1) healthy lean with normal IHTG content (Lean-NL; n = 12); (2) obese with normal IHTG content and normal glucose tolerance (Ob-NL; n = 25); and (3) obese with NAFLD and abnormal glucose metabolism (Ob-NAFLD; n = 25). Abdominal SAT TG synthesis rates were greater (P < 0.05) in both the Ob-NL (65.9 ± 4.6 g/wk) and Ob-NAFLD groups (71.1 ± 6.7 g/wk) than the Lean-NL group (16.2 ± 2.8 g/wk) without a difference between the Ob-NL and Ob-NAFLD groups. Abdominal SAT collagen synthesis rate and the composite expression of genes encoding collagens progressively increased from the Lean-NL to the Ob-NL to the Ob-NAFLD groups and were greater in the Ob-NAFLD than the Ob-NL group (P < 0.05). Composite expression of collagen genes was inversely correlated with both hepatic and whole-body insulin sensitivity (P < 0.001). CONCLUSIONS: AT expandability is not impaired in persons with obesity and NAFLD. However, SAT fibrogenesis is greater in persons with obesity and NAFLD than in those with obesity and normal IHTG content, and is inversely correlated with both hepatic and whole-body insulin sensitivity.

The muscle anabolic effect of protein ingestion during a hyperinsulinaemic euglycaemic clamp in middle-aged women is not caused by leucine alone.

KEY POINTS: It has been suggested that leucine is primarily responsible for the increase in muscle protein synthesis after protein ingestion because leucine uniquely activates the mTOR-p70S6K signalling cascade. We compared the effects of ingesting protein or an amount of leucine equal to that in the protein during a hyperinsulinaemic-euglycaemic clamp (to eliminate potential confounding as a result of differences in the insulinogenic effect of protein and leucine ingestion) on muscle anabolic signalling and protein turnover in 28 women. We found that protein, but not leucine, ingestion increased muscle p-mTORSer2448 and p-p70S6KThr389 , although only protein, and not leucine, ingestion decreased muscle p-eIF2αSer51 and increased muscle protein synthesis. ABSTRACT: It has been suggested that leucine is primarily responsible for the increase in muscle protein synthesis (MPS) after protein ingestion because leucine uniquely activates the mTOR-p70S6K signalling cascade. We tested this hypothesis by measuring muscle p-mTORSer2448 , p-p70S6KThr389 and p-eIF2αSer51 , as well as protein turnover (by stable isotope labelled amino acid tracer infusion in conjunction with leg arteriovenous blood and muscle tissue sampling), in 28 women who consumed either 0.45 g protein kg-1 fat-free mass (containing 0.0513 g leucine kg-1 fat-free mass) or a control drink (n = 14) or 0.0513 g leucine kg-1 fat-free mass or a control drink (n = 14) during a hyperinsulinaemic-euglycaemic clamp procedure (HECP). Compared to basal conditions, the HECP alone (without protein or leucine ingestion) suppressed muscle protein breakdown by ∼20% and increased p-mTORSer2448 and p-p70S6KThr389 by >50% (all P < 0.05) but had no effect on p-eIF2αSer51 and MPS. Both protein and leucine ingestion further increased p-mTORSer2448 and p-p70S6KThr389 , although only protein, and not leucine, ingestion decreased (by ∼35%) p-eIF2αSer51 and increased (by ∼100%) MPS (all P < 0.05). Accordingly, leg net protein balance changed from negative (loss) during basal conditions to equilibrium during the HECP alone and the HECP with concomitant leucine ingestion and to positive (gain) during the HECP with concomitant protein ingestion. These results provide new insights into the regulation of MPS by demonstrating that leucine and mTOR signalling alone are not responsible for the muscle anabolic effect of protein ingestion during physiological hyperinsulinaemia, most probably because they fail to signal to eIF2α to initiate translation and/or additional amino acids are needed to sustain translation.

Effect of hyperinsulinaemia-hyperaminoacidaemia on leg muscle protein synthesis and breakdown: reassessment of the two-pool arterio-venous balance model.

Accurate measurement of muscle protein turnover is critical for understanding the physiological processes underlying muscle atrophy and hypertrophy. Several mathematical approaches, used in conjunction with a tracer amino acid infusion, have been described to derive protein synthesis and breakdown rates from a two-pool (artery-vein) model. Despite apparently common underlying principles, these approaches differ significantly (some seem to not take into account arterio-venous shunting of amino acids, which comprises ∼80-90% of amino acids appearing in the vein) and most do not specify how tracer enrichment (i.e. mole percent excess (MPE) or tracer-to-tracee ratio (TTR)) and amino acid concentration (i.e. unlabelled only or total labelled plus unlabelled) should be expressed, which could have a significant impact on the outcome when using stable isotope labelled tracers. We developed equations that avoid these uncertainties and used them to calculate leg phenylalanine (Phe) kinetics in subjects who received a [(2) H5 ]Phe tracer infusion during postabsorptive conditions and during a hyperinsulinaemic-euglycaemic clamp with concomitant protein ingestion. These results were compared with those obtained by analysing the same data with previously reported equations. Only some of them computed the results correctly when used with MPE as the enrichment measure and total (tracer+tracee) Phe concentrations; errors up to several-fold in magnitude were noted when the same approaches were used in conjunction with TTR and/or unlabelled concentration only, or when using the other approaches (irrespective of how concentration and enrichment are expressed). Our newly developed equations should facilitate accurate calculation of protein synthesis and breakdown rates.

Impaired plasma glucose clearance is a key determinant of fasting hyperglycemia in people with obesity.

OBJECTIVE: The objective of this study was to evaluate the relative importance of the basal rate of glucose appearance (Ra) in the circulation and the basal rate of plasma glucose clearance in determining fasting plasma glucose concentration in people with obesity and different fasting glycemic statuses. METHODS: The authors evaluated basal glucose kinetics in 33 lean people with normal fasting glucose (<100 mg/dL; Lean < 100 group) and 206 people with obesity and normal fasting glucose (Ob < 100 group, n = 118), impaired fasting glucose (100-125 mg/dL; Ob 100-125 group, n = 66), or fasting glucose diagnostic of diabetes (≥126 mg/dL; Ob ≥ 126 group, n = 22). RESULTS: Although there was a large (up to three-fold) range in glucose Ra within each group, the ranges in glucose concentration in the Lean < 100, Ob < 100, and Ob 100-125 groups were small because of a close relationship between glucose Ra and clearance rate. However, the glucose clearance rate at any Ra value was lower in the hyperglycemic than the normoglycemic groups. In the Ob ≥ 126 group, plasma glucose concentration was primarily determined by glucose Ra, because glucose clearance was markedly attenuated. CONCLUSIONS: Fasting hyperglycemia in people with obesity represents a disruption of the precisely regulated integration of glucose production and clearance rates.

Cardiometabolic characteristics of people with metabolically healthy and unhealthy obesity.

There is considerable heterogeneity in the cardiometabolic abnormalities associated with obesity. We evaluated multi-organ system metabolic function in 20 adults with metabolically healthy obesity (MHO; normal fasting glucose and triglycerides, oral glucose tolerance, intrahepatic triglyceride content, and whole-body insulin sensitivity), 20 adults with metabolically unhealthy obesity (MUO; prediabetes, hepatic steatosis, and whole-body insulin resistance), and 15 adults who were metabolically healthy lean. Compared with MUO, people with MHO had (1) altered skeletal muscle biology (decreased ceramide content and increased expression of genes involved in BCAA catabolism and mitochondrial structure/function); (2) altered adipose tissue biology (decreased expression of genes involved in inflammation and extracellular matrix remodeling and increased expression of genes involved in lipogenesis); (3) lower 24-h plasma glucose, insulin, non-esterified fatty acids, and triglycerides; (4) higher plasma adiponectin and lower plasma PAI-1 concentrations; and (5) decreased oxidative stress. These findings provide a framework of potential mechanisms responsible for MHO and the metabolic heterogeneity of obesity. This study was registered at ClinicalTrials.gov (NCT02706262).

The effect of sodium acetate ingestion on the metabolic response to prolonged moderate-intensity exercise in humans.

At rest, administration of the short-chain fatty acid acetate suppresses fat oxidation without affecting carbohydrate utilization. The combined effect of increased acetate availability and exercise on substrate utilization is, however, unclear. With local ethics approval, we studied the effect of ingesting either sodium acetate (NaAc) or sodium bicarbonate (NaHCO3) at a dose of 4 mmol·kg-1 body mass 90 min before completing 120 min of exercise at 50% VO2peak. Six healthy young men completed the trials after an overnight fast and ingested the sodium salts in randomized order. As expected NaAc ingestion decreased resting fat oxidation (mean ± SD; 0.09 ± 0.02 vs. 0.07 ± 0.02 g·min-1 pre- and post-ingestion respectively, p < .05) with no effect upon carbohydrate utilization. In contrast, NaHCO3 ingestion had no effect on substrate utilization at rest. In response to exercise, fat and CHO oxidation increased in both trials, but fat oxidation was lower (0.16 ± 0.10 vs. 0.29 ± 0.11 g·min-1, p < .05) and carbohydrate oxidation higher (1.67 ± 0.35 vs. 1.44 ± 0.22 g·min-1, p < .05) in the NaAc trial compared with the NaHCO3 trial during the first 15 min of exercise. Over the final 75 min of exercise an increase in fat oxidation and decrease in carbohydrate oxidation was observed only in the NaAc trial. These results demonstrate that increasing plasma acetate concentration suppresses fat oxidation both at rest and at the onset of moderate-intensity exercise.

Metabolically Healthy Obesity is not a Myth.

People with obesity who do not have the metabolic syndrome or components of the metabolic syndrome have been characterized as having metabolically healthy obesity (MHO). However, the existence of MHO has been questioned because people with MHO are at greater risk of developing diabetes and fatal cardiovascular disease than people who are lean and healthy. Here we report findings from a 25-year-old woman with rigorously defined MHO (normal oral glucose tolerance, insulin sensitivity [assessed using the hyperinsulinemic-euglycemic clamp procedure], plasma triglyceride, and intrahepatic triglyceride content) evaluated at baseline (body mass index, 37.7 kg/m2) and 5 years later, after a 32% (30.8 kg) increase in body mass (BMI, 49.6 kg/m2). Weight gain did not have adverse effects on fasting plasma glucose, oral glucose tolerance, ß-cell function, insulin sensitivity, plasma triglyceride, intrahepatic triglyceride content, or carotid intima-media thickness. Adipose tissue expression of genes involved in extracellular matrix formation remained unchanged. Adipose tissue expression of several inflammation-related genes increased by more than 30%, but was not associated with a corresponding increase in plasma cytokine concentrations, with the exception of IL-6 and C-reactive protein. The present case study demonstrates that some people with obesity are resistant to the adverse cardiometabolic effects of excess adiposity and marked weight gain.

Short-term Intensive Lifestyle Therapy in a Worksite Setting Improves Cardiometabolic Health in People With Obesity.

Context: The Pritikin Program, which provides intensive lifestyle therapy, has been shown to improve cardiometabolic outcomes when provided as a residential program. Objective: The purpose of the present study was to conduct a short-term, randomized, controlled trial to evaluate the feasibility and clinical efficacy of treatment with the Pritikin Program in an outpatient worksite setting. Methods: Cardiometabolic outcomes were evaluated in people with overweight/obesity and ≥2 metabolic abnormalities (high triglycerides, low high-density lipoprotein (HDL) cholesterol, high blood pressure, HbA1c > 5.7%), before and after they were randomized to 6 weeks of standard care (n = 26) or intensive lifestyle therapy, based on the Pritikin Program (n = 28). Participants in the lifestyle intervention group were provided all food as packed-out meals and participated in group nutrition, behavioral education, cooking classes, and exercise sessions 3 times per week at a worksite location. Results: Compared with standard care, intensive lifestyle therapy decreased body weight (-5.0% vs -0.5%), HbA1c (-15.5% vs +2.3%), plasma total cholesterol (-9.8% vs +7.7%), low-density lipoprotein cholesterol (-10.3% vs +9.3%) and triglyceride (-21.7% vs +3.0%) concentrations, and systolic blood pressure (-7.0% vs 0%) (all P values < .02), and increased exercise tolerance (time to exhaustion walking on a treadmill by +23.7% vs +4.5%; P < .001). Conclusion: This study demonstrates the feasibility and clinical effectiveness of short-term, intensive outpatient lifestyle therapy in people with overweight/obesity and increased risk of coronary heart disease when all food is provided and the intervention is conducted at a convenient worksite setting.

Dorsal striatal response to taste is modified by obesity and insulin resistance.

OBJECTIVE: In preclinical models, insulin resistance in the dorsal striatum (DS) contributes to overeating. Although human studies support the concept of central insulin resistance, they have not investigated its effect on consummatory reward-induced brain activity. METHODS: Taste-induced activation was assessed in the caudate and putamen of the DS with blood oxygen level-dependent (BOLD) functional magnetic resonance imaging. Three phenotypically distinct groups were studied: metabolically healthy lean, metabolically healthy obesity, and metabolically unhealthy obesity (MUO; presumed to have central insulin resistance). Participants with MUO also completed a weight loss intervention followed by a second functional magnetic resonance imaging session. RESULTS: The three groups were significantly different at baseline consistent with the design. The metabolically healthy lean group had a primarily positive BOLD response, the MUO group had a primarily negative BOLD response, and the metabolically healthy obesity group had a response in between the two other groups. Food craving was predicted by taste-induced activation. After weight loss in the MUO group, taste-induced activation increased in the DS. CONCLUSIONS: These data support the hypothesis that insulin resistance and obesity contribute to aberrant responses to taste in the DS, which is only partially attenuated by weight loss. Aberrant responses to food exposure may be a barrier to weight loss.

Dietary weight loss-induced improvements in metabolic function are enhanced by exercise in people with obesity and prediabetes.

The additional therapeutic effects of regular exercise during a dietary weight loss program in people with obesity and prediabetes are unclear. Here, we show that whole-body (primarily muscle) insulin sensitivity (primary outcome) was 2-fold greater (P = 0.006) after 10% weight loss induced by calorie restriction plus exercise training (Diet+EX; n = 8, 6 women) than 10% weight loss induced by calorie restriction alone (Diet-ONLY; n = 8, 4 women) in participants in two concurrent studies. The greater improvement in insulin sensitivity was accompanied by increased muscle expression of genes involved in mitochondrial biogenesis, energy metabolism and angiogenesis (secondary outcomes) in the Diet+EX group. There were no differences between groups in plasma branched-chain amino acids or markers of inflammation, and both interventions caused similar changes in the gut microbiome. Few adverse events were reported. These results demonstrate that regular exercise during a diet-induced weight loss program has profound additional metabolic benefits in people with obesity and prediabetes.Trial Registration: ClinicalTrials.gov (NCT02706262 and NCT02706288).

Adipocyte lipin 1 is positively associated with metabolic health in humans and regulates systemic metabolism in mice.

Dysfunctional adipose tissue is believed to promote the development of hepatic steatosis and systemic insulin resistance, but many of the mechanisms involved are still unclear. Lipin 1 catalyzes the conversion of phosphatidic acid to diacylglycerol (DAG), the penultimate step of triglyceride synthesis, which is essential for lipid storage. Herein we found that adipose tissue LPIN1 expression is decreased in people with obesity compared to lean subjects and low LPIN1 expression correlated with multi-tissue insulin resistance and increased rates of hepatic de novo lipogenesis. Comprehensive metabolic and multi-omic phenotyping demonstrated that adipocyte-specific Lpin1-/- mice had a metabolically-unhealthy phenotype, including liver and skeletal muscle insulin resistance, hepatic steatosis, increased hepatic de novo lipogenesis, and transcriptomic signatures of nonalcoholic steatohepatitis that was exacerbated by high-fat diets. We conclude that adipocyte lipin 1-mediated lipid storage is vital for preserving adipose tissue and systemic metabolic health and its loss predisposes mice to nonalcoholic steatohepatitis.

Steatosis drives monocyte-derived macrophage accumulation in human metabolic dysfunction-associated fatty liver disease.

Background & Aims: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a common complication of obesity with a hallmark feature of hepatic steatosis. Recent data from animal models of MAFLD have demonstrated substantial changes in macrophage composition in the fatty liver. In humans, the relationship between liver macrophage heterogeneity and liver steatosis is less clear. Methods: Liver tissue from 21 participants was collected at time of bariatric surgery and analysed using flow cytometry, immunofluorescence, and H&E microscopy. Single-cell RNA sequencing was also conducted on a subset of samples (n = 3). Intrahepatic triglyceride content was assessed via MRI and tissue histology. Mouse models of hepatic steatosis were used to investigate observations made from human liver tissue. Results: We observed variable degrees of liver steatosis with minimal fibrosis in our participants. Single-cell RNA sequencing revealed four macrophage clusters that exist in the human fatty liver encompassing Kupffer cells and monocyte-derived macrophages (MdMs). The genes expressed in these macrophage subsets were similar to those observed in mouse models of MAFLD. Hepatic CD14+ monocyte/macrophage number correlated with the degree of steatosis. Using mouse models of early liver steatosis, we demonstrate that recruitment of MdMs precedes Kupffer cell loss and liver damage. Electron microscopy of isolated macrophages revealed increased lipid accumulation in MdMs, and ex vivo lipid transfer experiments suggested that MdMs may serve a distinct role in lipid uptake during MAFLD. Conclusions: The human liver in MAFLD contains macrophage subsets that align well with those that appear in mouse models of fatty liver disease. Recruited myeloid cells correlate well with the degree of liver steatosis in humans. MdMs appear to participate in lipid uptake during early stages of MALFD. Impact and implications: Metabolic dysfunction associated fatty liver disease (MAFLD) is extremely common; however, the early inflammatory responses that occur in human disease are not well understood. In this study, we investigated macrophage heterogeneity in human livers during early MAFLD and demonstrated that similar shifts in macrophage subsets occur in human disease that are similar to those seen in preclinical models. These findings are important as they establish a translational link between mouse and human models of disease, which is important for the development and testing of new therapeutic approaches for MAFLD.

Testosterone increases the muscle protein synthesis rate but does not affect very-low-density lipoprotein metabolism in obese premenopausal women.

Men and women with hyperandrogenemia have a more proatherogenic plasma lipid profile [e.g., greater triglyceride (TG) and total and low-density lipoprotein-cholesterol and lower high-density lipoprotein-cholesterol concentrations] than healthy premenopausal women. Furthermore, castration of male rats markedly reduces testosterone availability below normal and decreases plasma TG concentration, and testosterone replacement reverses this effect. Testosterone is, therefore, thought to be an important regulator of plasma lipid homeostasis. However, little is known about the effect of testosterone on plasma TG concentration and kinetics. Furthermore, testosterone is a potent skeletal muscle protein anabolic agent in men, but its effect on muscle protein turnover in women is unknown. We measured plasma lipid concentrations, hepatic very low density lipoprotein (VLDL)-TG and VLDL-apolipoprotein B-100 secretion rates, and the muscle protein fractional synthesis rate in 10 obese women before and after trandermal testosterone (1.25 g of 1% AndroGel daily) treatment for 3 wk. Serum total and free testosterone concentrations increased (P < 0.05) by approximately sevenfold in response to testosterone treatment, reaching concentrations that are comparable to those in women with hyperandrogenemia, but lower than the normal range for eugonadal men. Except for a small (∼10%) decrease in plasma high-density lipoprotein particle and cholesterol concentrations (P < 0.04), testosterone therapy had no effect on plasma lipid concentrations, lipoprotein particle sizes, and hepatic VLDL-TG and VLDL-apolipoprotein B-100 secretion rates (all P > 0.05); the muscle protein fractional synthesis rate, however, increased by ∼45% (P < 0.001). We conclude that testosterone is a potent skeletal muscle protein anabolic agent, but not an important regulator of plasma lipid homeostasis in obese women.

ß Cell function and plasma insulin clearance in people with obesity and different glycemic status.

BackgroundIt is unclear how excess adiposity and insulin resistance affect ß cell function, insulin secretion, and insulin clearance in people with obesity.MethodsWe used a hyperinsulinemic-euglycemic clamp procedure and a modified oral glucose tolerance test to evaluate the interrelationships among obesity, insulin sensitivity, insulin kinetics, and glycemic status in 5 groups of individuals: normoglycemic lean and obese individuals with (a) normal fasting glucose and normal glucose tolerance (Ob-NFG-NGT), (b) NFG and impaired glucose tolerance (Ob-NFG-IGT), (c) impaired fasting glucose and IGT (Ob-IFG-IGT), or (d) type 2 diabetes (Ob-T2D).ResultsGlucose-stimulated insulin secretion (GSIS), an assessment of ß cell function, was greater in the Ob-NFG-NGT and Ob-NFG-IGT groups than in the lean group, even when insulin sensitivity was matched in the obese and lean groups. Insulin sensitivity, not GSIS, was decreased in the Ob-NFG-IGT group compared with the Ob-NFG-NGT group, whereas GSIS, not insulin sensitivity, was decreased in the Ob-IFG-IGT and Ob-T2D groups compared with the Ob-NFG-NGT and Ob-NFG-IGT groups. Insulin clearance was directly related to insulin sensitivity and inversely related to the postprandial increase in insulin secretion and plasma insulin concentration.ConclusionIncreased adiposity per se, not insulin resistance, enhanced insulin secretion in people with obesity. The obesity-induced increase in insulin secretion, in conjunction with a decrease in insulin clearance, sufficiently raised the plasma insulin concentrations needed to maintain normoglycemia in individuals with moderate, but not severe, insulin resistance. A deterioration in ß cell function, not a decrease in insulin sensitivity, was a determinant of IFG and ultimately leads to T2D.CLINICAL TRIALS REGISTRATIONClinicalTrials.gov NCT02706262, NCT04131166, and NCT01977560.FUNDINGNIH (P30 DK056341, P30 DK020579, and UL1 TR000448); American Diabetes Association (1-18-ICTS-119); Longer Life Foundation; Pershing Square Foundation; and Washington University-Centene ARCH Personalized Medicine Initiative (P19-00559).

Worksite-based intensive lifestyle therapy has profound cardiometabolic benefits in people with obesity and type 2 diabetes.

Lifestyle therapy (energy restriction and exercise) is the cornerstone of therapy for people with type 2 diabetes (T2D) but is difficult to implement. We conducted an 8-month randomized controlled trial in persons with obesity and T2D (17 women and 1 man) to determine the therapeutic effects and potential mechanisms of intensive lifestyle therapy on cardiometabolic function. Intensive lifestyle therapy was conducted at the worksite to enhance compliance and resulted in marked (17%) weight loss and beneficial changes in body fat mass, intrahepatic triglyceride content, cardiorespiratory fitness, muscle strength, glycemic control, ß cell function, and multi-organ insulin sensitivity, which were associated with changes in muscle NAD+ biosynthesis, sirtuin signaling, and mitochondrial function and in adipose tissue remodeling. These findings demonstrate that intensive lifestyle therapy provided at the worksite has profound therapeutic clinical and physiological effects in people with T2D, which are likely mediated by specific alterations in skeletal muscle and adipose tissue biology.

Silencing alanine transaminase 2 in diabetic liver attenuates hyperglycemia by reducing gluconeogenesis from amino acids.

Hepatic gluconeogenesis from amino acids contributes significantly to diabetic hyperglycemia, but the molecular mechanisms involved are incompletely understood. Alanine transaminases (ALT1 and ALT2) catalyze the interconversion of alanine and pyruvate, which is required for gluconeogenesis from alanine. We find that ALT2 is overexpressed in the liver of diet-induced obese and db/db mice and that the expression of the gene encoding ALT2 (GPT2) is downregulated following bariatric surgery in people with obesity. The increased hepatic expression of Gpt2 in db/db liver is mediated by activating transcription factor 4, an endoplasmic reticulum stress-activated transcription factor. Hepatocyte-specific knockout of Gpt2 attenuates incorporation of 13C-alanine into newly synthesized glucose by hepatocytes. In vivo Gpt2 knockdown or knockout in liver has no effect on glucose concentrations in lean mice, but Gpt2 suppression alleviates hyperglycemia in db/db mice. These data suggest that ALT2 plays a significant role in hepatic gluconeogenesis from amino acids in diabetes.

Small molecule SWELL1 complex induction improves glycemic control and nonalcoholic fatty liver disease in murine Type 2 diabetes.

Type 2 diabetes is associated with insulin resistance, impaired pancreatic ß-cell insulin secretion, and nonalcoholic fatty liver disease. Tissue-specific SWELL1 ablation impairs insulin signaling in adipose, skeletal muscle, and endothelium, and impairs ß-cell insulin secretion and glycemic control. Here, we show that ICl,SWELL and SWELL1 protein are reduced in adipose and ß-cells in murine and human diabetes. Combining cryo-electron microscopy, molecular docking, medicinal chemistry, and functional studies, we define a structure activity relationship to rationally-design active derivatives of a SWELL1 channel inhibitor (DCPIB/SN-401), that bind the SWELL1 hexameric complex, restore SWELL1 protein, plasma membrane trafficking, signaling, glycemic control and islet insulin secretion via SWELL1-dependent mechanisms. In vivo, SN-401 restores glycemic control, reduces hepatic steatosis/injury, improves insulin-sensitivity and insulin secretion in murine diabetes. These findings demonstrate that SWELL1 channel modulators improve SWELL1-dependent systemic metabolism in Type 2 diabetes, representing a first-in-class therapeutic approach for diabetes and nonalcoholic fatty liver disease.