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BACKGROUND. Mirabegron is a [beta]3-adrenergic receptor ([beta]3-AR) agonist approved only for the treatment of overactive bladder. Encouraging preclinical results suggest that [beta]3-AR agonists could also improve obesity-related metabolic disease by increasing brown adipose tissue (BAT) thermogenesis, white adipose tissue (WAT) lipolysis, and insulin sensitivity. METHODS. We treated 14 healthy women of diverse ethnicities (27.5 [+ or -] 1.1 years of age, BMI of 25.4 [+ or -] 1.2 kg/[m.sup.2]) with 100 mg mirabegron (Myrbetriq extended-release tablet, Astellas Pharma) for 4 weeks in an open-label study. The primary endpoint was the change in BAT metabolic activity as measured by [[sup.18]F]-2-fluoro -D-2-deoxy-D-glucose ([sup.18]F-FDG) PET/CT. Secondary endpoints included resting energy expenditure (REE), plasma metabolites, and glucose and insulin metabolism as assessed by a frequently sampled intravenous glucose tolerance test. RESULTS. Chronic mirabegron therapy increased BAT metabolic activity. Whole-body REE was higher, without changes in body weight or composition. Additionally, there were elevations in plasma levels of the beneficial lipoprotein biomarkers HDL and ApoA1, as well as total bile acids. Adiponectin, a WAT-derived hormone that has antidiabetic and antiinflammatory capabilities, increased with acute treatment and was 35% higher upon completion of the study. Finally, an intravenous glucose tolerance test revealed higher insulin sensitivity, glucose effectiveness, and insulin secretion. CONCLUSION. These findings indicate that human BAT metabolic activity can be increased after chronic pharmacological stimulation with mirabegron and support the investigation of [beta]3-AR agonists as a treatment for metabolic disease. TRIAL REGISTRATION. Clinicaltrials.gov NCT03049462. FUNDING. This work was supported by grants from the Intramural Research Program of the NIDDK, NIH (DK075112, DK075116, DK071013, and DK071014)., Introduction The rising rates of obesity are a global health epidemic. In the US alone, by 2030 it is predicted that 86% of adults will be overweight or obese (1). [...]

BACKGROUND. Recombinant leptin (metreleptin) ameliorates hyperphagia and metabolic abnormalities in leptin-deficient humans with lipodystrophy. We aimed to determine whether metreleptin improves glucose and lipid metabolism in humans when food intake is held constant. METHODS. Patients with lipodystrophy were hospitalized for 19 days, with food intake held constant by a controlled diet in an inpatient metabolic ward. In a nonrandomized, crossover design, patients previously treated with metreleptin (n = 8) were continued on metreleptin for 5 days and then taken off metreleptin for the next 14 days (withdrawal cohort). This order was reversed in metreleptin-naive patients (n = 14), who were reevaluated after 6 months of metreleptin treatment on an ad libitum diet (initiation cohort). Outcome measurements included insulin sensitivity by hyperinsulinemic-euglycemic clamp, fasting glucose and triglyceride levels, lipolysis measured using isotopic tracers, and liver fat by magnetic resonance spectroscopy. RESULTS. With food intake constant, peripheral insulin sensitivity decreased by 41% after stopping metreleptin for 14 days (withdrawal cohort) and increased by 32% after treatment with metreleptin for 14 days (initiation cohort). In the initiation cohort only, metreleptin decreased fasting glucose by 11% and triglycerides by 41% and increased hepatic insulin sensitivity. Liver fat decreased from 21.8% to 18.7%. In the initiation cohort, changes in lipolysis were not independent of food intake, but after 6 months of metreleptin treatment on an ad libitum diet, lipolysis decreased by 30% (palmitate turnover) to 35% (glycerol turnover). CONCLUSION. Using lipodystrophy as a human model of leptin deficiency and replacement, we show that metreleptin improves insulin sensitivity and decreases hepatic and circulating triglycerides and that these improvements are independent of its effects on food intake. TRIAL REGISTRATION. ClinicalTrials.gov NCT01778556 FUNDING. This research was supported by the intramural research program of the NIDDK., Introduction Leptin is an adipocyte-derived hormone that signals overall body energy sufficiency (1) and acute energy balance (2). Leptin-deficient states, such as starvation or mutations in the leptin gene, lead [...]

Black women, compared with White women, have high rates of whole-body insulin resistance but a lower prevalence of fasting hyperglycemia and hepatic steatosis. This dissociation of whole-body insulin resistance from fasting hyperglycemia may be explained by racial differences in gluconeogenesis, hepatic fat, or tissue-specific insulin sensitivity. Two groups of premenopausal federally employed women, without diabetes were studied. Using stable isotope tracers, [2H2O] and [6,62-H2]glucose, basal glucose production was partitioned into its components (gluconeogenesis and glycogenolysis) and basal whole-body lipolysis ([2H5]glycerol) was measured. Indices of insulin sensitivity, whole-body (SI), hepatic (HISIGPR), and adipose tissue, were calculated. Hepatic fat was measured by proton magnetic resonance spectroscopy. Black women had less hepatic fat and lower fractional and absolute gluconeogenesis. Whole-body SI, HISIGPR, and adipose tissue sensitivity were similar by race, but at any given level of whole-body SI, Black women had higher HISIGPR. Therefore, fasting hyperglycemia may be a less common early pathological feature of prediabetes in Black women compared with White women, because gluconeogenesis remains lower despite similar whole-body SI.