American Journal of Physiology. Endocrinology and Metabolism

One-anastomosis gastric bypass (OAGB) has gained importance as a safe and effective operation to treat morbid obesity. It is not known whether a long biliopancreatic limb (BPL) in OAGB surgery compared to a short BPL results in beneficial metabolic outcomes. 5-week-old male C57BL/6J mice fed a high-fat diet for 8 weeks underwent OAGB surgery with defined short and long BPL lengths, or sham surgery combined with caloric restriction. Weight loss, glucose tolerance, obesity-related comorbidities, endocrine effects, gut microbiota and bile acids were assessed...

Diabetic kidney disease (DKD) is a leading cause of chronic kidney disease and affects approximately 40% of diabetic individuals. Cases of DKD continue to rise globally as the prevalence of diabetes mellitus increases, with an estimated 415 million people living with diabetes in 2015 and a projected 642 million by 2040. DKD is associated with significant morbidity and mortality, representing 34% and 36% of all chronic kidney disease deaths in men and women, respectively. Common co-morbidities including hypertension and ageing-related nephron loss further complicate disease diagnosis and progression...

Spinophilin is an F-actin binding and protein phosphatase 1 (PP1) targeting protein that acts as a scaffold of PP1 to its substrates. Spinophilin knockout (Spino-/- ) mice have decreased fat mass, increased lean mass, and improved glucose tolerance, with no difference in feeding behaviors. While spinophilin is enriched in neurons, its roles in non-neuronal tissues, such as beta cells of the pancreatic islets, are unclear. We have corroborated and expanded upon previous studies to determine that Spino-/- mice have decreased weight gain and improved glucose tolerance in two different models of obesity...

Most studies on fat appetite have focused on long-chain triglycerides (LCTs) due to their obesogenic properties. Medium-chain triglycerides (MCTs), conversely, exhibit anti-obesogenic effects; however, the regulation of MCTs intake remains elusive. Here, we demonstrate that mice can distinguish between MCTs and LCTs, and the specific appetite for MCTs is governed by hepatic β-oxidation. We generated liver-specific medium-chain acyl-CoA dehydrogenase (MCAD)-deficient (MCADL-/- ) mice and analyzed their preference for MCTs and LCTs solutions using glyceryl trioctanoate (C8-TG), glyceryl tridecanoate (C10-TG), corn oil, and lard oil in two-bottle choice tests conducted over 8 days...

Hypothalamic proopiomelanocortin neurons are sensors of signals that reflect the energy stores in the body. Inducing mild stress in proopiomelanocortin neurons protect them from the damage promoted by the consumption of a high-fat diet, mitigating the development of obesity; however, the cellular mechanisms behind these effects are unknown. Here, we induced mild stress in a proopiomelanocortin neuron cell line by inhibiting Crif1. In proopiomelanocortin neurons exposed to high levels of palmitate, the partial inhibition of Crif1 reverted the defects in mitochondrial respiration and ATP production; this was accompanied by improved mitochondrial fusion/fission cycling...

OBJECTIVE: Obesity has become a major risk of global public health. SMEK1 is also known as a regulatory subunit of protein phosphatase 4 (PP4). Both PP4 and SMEK1 have been clarified many metabolic functions, including regulating the hepatic gluconeogenesis and glucose transporter gene expression in yeast. Whether SMEK1 participates in obesity and the broader metabolic role in mammals is unknown. Thus we investigated the function of SMEK1 in white adipose tissue and glucose uptake. METHODS: GWAS/GEPIA/GEO database was used to analyze the correlation between SMEK1 and metabolic phenotypes/lipid metabolism related genes/obesity...

We investigated if a bout of exercise in a hot environment (HEAT) would reduce the postprandial hyperglycemia induced by glucose ingestion. The hypothesis was that HEAT stimulating glycogen use would increase the disposal of the ingested glucose (i.e., OGTT; 75 g of glucose). Separated by at least 1 week, nine young-healthy individuals underwent three trials after an overnight fast in a randomized order. Two trials included 50 min of pedaling at 58±5% VO2MAX either in a thermoneutral (21±1ºC; NEUTRAL) or in a hot environment (33±1ºC; HEAT) eliciting similar energy expenditure (503±101 kcals)...

Glycogen is a form of energy storage for glucose in different tissues such as liver and skeletal muscle. It remains incompletely understood how glycogen impacts on adipose tissue functionality. Cold exposure elevated the expression of Gys1 which encodes glycogen synthase 1 in brown adipose tissue (BAT) and inguinal white adipose tissue (iWAT). The in vivo function of Gys1 was analyzed using a mouse model in which Gys1 was deleted specifically in adipose tissues. Under normal chow conditions, Gys1 deletion caused little changes to body weight and glucose metabolism...

Despite the fact that genes and the environment are known to play a central role in islet function, our knowledge of how these parameters interact to modulate insulin secretory function remains relatively poor. Presently, we performed ex vivo glucose-stimulated insulin secretion and insulin content assays in islets of 213 mice from 13 inbred mouse strains on chow, western diet, and ketogenic diet. Strikingly, among these 13 strains, islets from the commonly used C57BL/6J mouse strain were the least glucose responsive...

Long-term hyperglycemia in individuals with type 2 diabetes can detrimentally impact pulmonary function and muscle oxygenation. As a result, these factors can impede the body's adaptation to physical exertion. We aimed to evaluate the oxygen pathway during maximal exercise among overweight/obese individuals with uncomplicated type 2 diabetes, in comparison with a group of matched overweight/obese individuals without diabetes, specifically concentrating on the effects on pulmonary function and muscle oxygenation...

Loss of ovarian function imparts increased susceptibility to obesity and metabolic disease. These effects are largely attributed to decreased estradiol (E2 ), but the role of increased follicle stimulating hormone (FSH) in modulating energy balance has not been fully investigated. Previous work that blocked FSH binding to its receptor in mice suggested this hormone may play a part in modulating body weight and energy expenditure after ovariectomy. We used an alternate approach to isolate the individual and combined contributions of FSH and E2 in mediating energy imbalance and changes in tissue-level metabolic health...

Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of β cells by immune cells. The interactions among cells within the islets may be closely linked to the pathogenesis of T1D. In this study, we utilized single-cell RNA sequencing (scRNA-seq) to analyze the cellular heterogeneity within the islets of a T1D mouse model. We established a T1D mouse model induced by streptozotocin and identified cell subpopulations using scRNA-seq technology. Our results revealed 11 major cell types in the pancreatic islets of T1D mice, with heterogeneity observed in the alpha and beta cell subgroups, which may play a crucial role in the progression of T1D...

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease with increasing prevalence worldwide. NAFLD could develop from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH) causing fibrosis, cirrhosis and even hepatocellular carcinoma. However, the mechanism of NAFLD development was still not be fully defined. Recently, there are emerging evidence showing the dysregulated iron metabolism with elevated serum ferritin and ferroptosis are involved in the NAFLD. The iron metabolism and ferroptosis would shed some light on the mechanisms of NAFLD development...

There is increasing evidence linking bitter taste receptor (BTR) signalling to gut hormone secretion and glucose homeostasis. However, its effect on islet hormone secretion has been poorly characterised. This study investigated the effect of the bitter substance, denatonium benzoate (DB), on hormone secretion from mouse pancreatic islets and INS-1 832/13 cells. DB (0.5-1mM) augmented insulin secretion at both 2.8mM and 16.7mM glucose. This effect was no longer present at 5mM DB likely due to greater levels of cellular apoptosis...

In rodents, loss of estradiol (E2 ) reduces brown adipose tissue (BAT) metabolic activity. Whether E2 impacts BAT activity in women is not known. BAT oxidative metabolism was measured in premenopausal (N=27, 35±9 years, body mass index (BMI) = 26.0±5.3 kg/m2 ) and postmenopausal (N=25, 51±8 years, BMI = 28.0±5.0 kg/m2 ) women at room temperature (RT) and during acute cold exposure using [11 C]-acetate with positron emission tomography coupled with computed tomography (PET/CT). BAT glucose uptake was also measured during acute cold exposure using 2-deoxy-2-[18 F]fluoro-D-glucose ([18 F]FDG)...

Nausea and vomiting are primitive aspects of mammalian physiology and behavior that ensure survival. Unfortunately, both are ubiquitously present side effects of drug treatments for many chronic diseases with negative consequences on pharmacotherapy tolerance, quality of life, and prognosis. One of the most critical clinical examples is the profound emesis and nausea that occur in patients undergoing chemotherapy, which continue to be among the most distressing side effects, even with the use of modern anti-emetic medications...

Chronic kidney disease (CKD) is a debilitating condition associated with significant morbidity and mortality. In recent years, the kidney effects of incretin-based therapies, particularly glucagon-like peptide-1 receptor agonists (GLP-1RAs), have garnered substantial interest in the management of type 2 diabetes (T2D) and obesity. This review delves into the intricate interactions between the kidney, GLP-1RAs, and glucagon, shedding light on their mechanisms of action and potential kidney benefits. Both GLP-1 and glucagon, known for their opposing roles in regulating glucose homeostasis, improve systemic risk factors affecting the kidney, including adiposity, inflammation, oxidative stress, and endothelial function...

Metabolic-associated fatty liver disease (MAFLD) has been identified as risk factor of incident type 2 diabetes (T2D), but the underlying postprandial mechanisms remains unclear. We compared the glucose metabolism, insulin resistance, insulin secretion and insulin clearance post-oral glucose tolerance test (OGTT) between individuals with and without MAFLD. We included 50 individuals with a BMI between 25-40 kg/m2 and ≥1 metabolic alteration: increased fasting triglycerides or insulin, plasma glucose 5...

Signaling through Prostaglandin E2 EP3 receptor (EP3) actively contributes to the β-cell dysfunction of type 2 diabetes (T2D). In T2D models, full-body EP3 knockout mice have a significantly worse metabolic phenotype than wild-type controls due to hyperphagia and severe insulin resistance resulting from loss of EP3 in extra-pancreatic tissues, masking any potential beneficial effects of EP3 loss in the β-cell. We hypothesized β-cell-specific EP3 knockout (EP3 βKO) mice would be protected from high-fat diet (HFD)-induced glucose intolerance, phenocopying mice lacking the EP3 effector, Gɑz , which is much more limited in its tissue distribution...

Prenatal exposure to maternal diabetes has been identified as a cardiovascular risk factor. It is unclear if offspring exposed to diabetes in utero manifest a worse vascular outcome to a high salt (HS) diet. To test the hypothesis that in utero exposure to maternal diabetes facilitates salt-induced vascular dysfunction, we treated adult male wild-type offspring (DM_Exp, 6-months-old) of diabetic Ins2+/C96Y mice ( Akita mice) with HS (8% sodium chloride, 10-days) and analyzed endothelial function via wire myograph and cyclooxygenase (COX)-derived prostanoids pathway by ELISA, qPCR, and immunochemistry...