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In response to a meal, insulin drives hepatic glycogen synthesis to help regulate systemic glucose homeostasis. The mechanistic target of rapamycin complex 1 (mTORC1) is a well-established insulin target and contributes to the postprandial control of liver lipid metabolism, autophagy, and protein synthesis. However, its role in hepatic glucose metabolism is less understood. Here, we used metabolomics, isotope tracing, and mouse genetics to define a role for liver mTORC1 signaling in the control of postprandial glycolytic intermediates and glycogen deposition. We show that mTORC1 is required for glycogen synthase activity and glycogenesis. Mechanistically, hepatic mTORC1 activity promotes the feeding-dependent induction of Ppp1r3b, a gene encoding a phosphatase important for glycogen synthase activity whose polymorphisms are linked to human diabetes. Reexpression of Ppp1r3b in livers lacking mTORC1 signaling enhances glycogen synthase activity and restores postprandial glycogen content. mTORC1-dependent transcriptional control of Ppp1r3b is facilitated by FOXO1, a well characterized transcriptional regulator involved in the hepatic response to nutrient intake. Collectively, we identify a role for mTORC1 signaling in the transcriptional regulation of Ppp1r3b and the subsequent induction of postprandial hepatic glycogen synthesis., Introduction The liver is a central regulator of systemic glucose metabolism. Dysregulation of postprandial hepatic glucose metabolism contributes to the development of metabolic disorders, such as insulin resistance and type [...]

Adipose tissues are organs that have vital physiological roles in human health and disease. Functionally, white adipose tissue (WAT) is the principal repository for triglyceride energy, while brown adipose tissue [...]

BACKGROUND. Proglucagon can be processed to glucagon-like peptidel (GLP-1) within the islet, but its contribution to islet function in humans remains unknown. We sought to understand whether pancreatic GLP-1 alters islet function in humans and whether this is affected by type 2 diabetes. METHODS. We therefore studied individuals with and without type 2 diabetes on two occasions in random order. On one occasion, exendin 9-39, a competitive antagonist of the GLP-1 Receptor (GLP1R), was infused, while on the other, saline was infused. The tracer dilution technique ([3-[sup.3]H] glucose) was used to measure glucose turnover during fasting and during a hyperglycemic clamp. RESULTS. Exendin 9-39 increased fasting glucose concentrations; fasting islet hormone concentrations were unchanged, but inappropriate for the higher fasting glucose observed. In people with type 2 diabetes, fasting glucagon concentrations were markedly elevated and persisted despite hyperglycemia. This impaired suppression of endogenous glucose production by hyperglycemia. CONCLUSION. These data show that GLP1R blockade impairs islet function, implying that intra-islet GLP1R activation alters islet responses to glucose and does so to a greater degree in people with type 2 diabetes. TRIAL REGISTRATION. This study was registered at ClinicalTrials.gov NCT04466618. FUNDING. The study was primarily funded by NIH NIDDK DK126206. AV is supported by DK78646, DK116231 and DK126206. CDM was supported by MIUR (Italian Minister for Education) under the initiative 'Departments of Excellence' (Law 232/2016)., Introduction There are multiple strands of evidence that posttranslational processing of proglucagon in a-cells can yield glucagon-like peptidel (GLP-1) (1). Inflammation and caloric excess (2,3) induce prohormone convertase-1/3 (PC-1/3) in [...]

Circadian rhythms govern glucose homeostasis, and their dysregulation leads to complex metabolic diseases. Gut microbes exhibit diurnal rhythms that influence host circadian networks and metabolic processes, yet underlying mechanisms remain elusive. Here, we showed hierarchical, bidirectional communication among the liver circadian clock, gut microbes, and glucose homeostasis in mice. To assess this relationship, we utilized mice with liver-specific deletion of the core circadian clock gene Bmal1 via Albumin-cre maintained in either conventional or germ-free housing conditions. The liver clock, but not the forebrain clock, required gut microbes to drive glucose clearance and gluconeogenesis. Liver clock dysfunctionality expanded proportions and abundances of oscillating microbial features by 2-fold relative to that in controls. The liver clock was the primary driver of differential and rhythmic hepatic expression of glucose and fatty acid metabolic pathways. Absent the liver clock, gut microbes provided secondary cues that dampened these rhythms, resulting in reduced lipid fuel utilization relative to carbohydrates. All together, the liver clock transduced signals from gut microbes that were necessary for regulating glucose and lipid metabolism and meeting energy demands over 24 hours., Introduction Circadian rhythms are essential to nearly all life, coordinating behavior and compartmentalizing physiological processes that govern energy balance over a 24-hour period (1). Self-sustaining and cell-autonomous, circadian rhythms serve [...]

Dietary interventions can change metabolite levels in the tumour microenvironment, which might then affect cancer cell metabolism to alter tumour growth.sup.1-5. Although caloric restriction (CR) and a ketogenic diet (KD) are often thought to limit tumour progression by lowering blood glucose and insulin levels.sup.6-8, we found that only CR inhibits the growth of select tumour allografts in mice, suggesting that other mechanisms contribute to tumour growth inhibition. A change in nutrient availability observed with CR, but not with KD, is lower lipid levels in the plasma and tumours. Upregulation of stearoyl-CoA desaturase (SCD), which synthesises monounsaturated fatty acids, is required for cancer cells to proliferate in a lipid-depleted environment, and CR also impairs tumour SCD activity to cause an imbalance between unsaturated and saturated fatty acids to slow tumour growth. Enforcing cancer cell SCD expression or raising circulating lipid levels through a higher-fat CR diet confers resistance to the effects of CR. By contrast, although KD also impairs tumour SCD activity, KD-driven increases in lipid availability maintain the unsaturated to saturated fatty acid ratios in tumours, and changing the KD fat composition to increase tumour saturated fatty acid levels cooperates with decreased tumour SCD activity to slow tumour growth. These data suggest that diet-induced mismatches between tumour fatty acid desaturation activity and the availability of specific fatty acid species determine whether low glycaemic diets impair tumour growth. Lien et al. show that low glycemic diets can reduce tumour growth by deregulating lipid metabolism., Author(s): Evan C. Lien [sup.1] , Anna M. Westermark [sup.1] , Yin Zhang [sup.2] [sup.3] , Chen Yuan [sup.2] , Zhaoqi Li [sup.1] [sup.4] , Allison N. Lau [sup.1] , [...]

Adipocytes increase energy expenditure in response to prolonged sympathetic activation via persistent expression of uncoupling protein 1 (UCP1).sup.1,2. Here we report that the regulation of glycogen metabolism by catecholamines is critical for UCP1 expression. Chronic [beta]-adrenergic activation leads to increased glycogen accumulation in adipocytes expressing UCP1. Adipocyte-specific deletion of a scaffolding protein, protein targeting to glycogen (PTG), reduces glycogen levels in beige adipocytes, attenuating UCP1 expression and responsiveness to cold or [beta]-adrenergic receptor-stimulated weight loss in obese mice. Unexpectedly, we observed that glycogen synthesis and degradation are increased in response to catecholamines, and that glycogen turnover is required to produce reactive oxygen species leading to the activation of p38 MAPK, which drives UCP1 expression. Thus, glycogen has a key regulatory role in adipocytes, linking glucose metabolism to thermogenesis. Increased glycogen metabolism in adipocytes leads to expression of uncoupling protein 1, thereby linking glucose metabolism to thermogenesis., Author(s): Omer Keinan [sup.1] , Joseph M. Valentine [sup.1] , Haopeng Xiao [sup.2] [sup.3] , Sushil K. Mahata [sup.4] , Shannon M. Reilly [sup.1] , Mohammad Abu-Odeh [sup.1] , Julia [...]

We aimed to determine the metabolic differences between male and female rats after ileal interposition surgery and determine whether the remission of insulin resistance after ileal interposition is dependent on melanocortin-4 receptor signaling in both male and female rats. All age-matched male and female rats were treated with either sham or ileal interposition surgery. Glucose tolerance tests and body composition analysis were then performed. Our results indicated a loss of Mc4r function in both male and female rats induced obesity; male knockout rats with sham surgery, not female knockout rats with sham surgery, showed impaired glucose tolerance; insulin resistance of both knockout sham rats and pairfeeding sham rats is significantly higher than that of knockout interposition rats and pairfeeding interposition rats respectively in both male and female rats; interposition surgery decreased both fat percentage and fat mass in female rats, not in male rats, in the long run. In conclusion, Melanocortin-4 Receptor signaling is not necessary for the underlying beneficial effects of ileal interposition on glucose metabolism and insulin resistance. Female rats might get more stable benefits than male rats after the surgery., INTRODUCTION Melanocortin-4 receptor (MC4R) in the brain plays a critical role in regulating energy homeostasis (1-3). MC4R gene mutations have a prevalence of 1-2.5% in people with BMI of greater [...]