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Objective: Pancreatic β-cell dysfunction is a central feature in the pathogenesis of type 2 diabetes (T2D). Accumulating evidence indicates that β-site APP-cleaving enzyme 2 (BACE2) inhibition exerts a beneficial effect on β-cells in different models of T2D. Thus, targeting BACE2 may represent a potential therapeutic strategy for the treatment of this disease. Here, we aimed to investigate the effects of BACE2 suppression on glucose homeostasis in a model of diet-induced obesity., Methods: BACE2 knock-out (BKO) and wild-type (WT) mice were fed with a high-fat diet (HFD) for 2 or 16 weeks. Body weight, food intake, respiratory exchange ratio, locomotor activity, and energy expenditure were determined. Glucose homeostasis was evaluated by glucose and insulin tolerance tests. β-cell proliferation was assessed by Ki67-positive nuclei, and β-cell function was determined by measuring glucose-stimulated insulin secretion. Leptin sensitivity was evaluated by quantifying food intake and body weight after an intraperitoneal leptin injection. Neuropeptide gene expression and insulin signaling in the mediobasal hypothalamus were determined by qPCR and Akt phosphorylation, respectively., Results: After 16 weeks of HFD feeding, BKO mice exhibited an exacerbated body weight gain and hyperphagia, in comparison to WT littermates. Glucose tolerance was similar in both groups, whereas HFD-induced hyperinsulinemia, insulin resistance, and β-cell expansion were more pronounced in BKO mice. In turn, leptin-induced food intake inhibition and hypothalamic insulin signaling were impaired in BKO mice, regardless of the diet, in accordance with deregulation of the expression of hypothalamic neuropeptide genes. Importantly, BKO mice already showed increased β-cell proliferation and glucose-stimulated insulin secretion with respect to WT littermates after two weeks of HFD feeding, before the onset of obesity., Conclusions: Collectively, these results reveal that BACE2 suppression in an obesogenic setting leads to exacerbated body weight gain, hyperinsulinemia, and insulin resistance. Thus, we conclude that inhibition of BACE2 may aggravate the adverse metabolic effects associated with obesity., (Copyright © 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Amyloid deposits in pancreatic islets, mainly formed by human islet amyloid polypeptide (hIAPP) aggregation, have been associated with loss of β-cell mass and function, and are a pathological hallmark of type 2 diabetes (T2D). Treatment with chaperones has been associated with a decrease in endoplasmic reticulum stress leading to improved glucose metabolism. The aim of this work was to investigate whether the chemical chaperone 4-phenylbutyrate (PBA) prevents glucose metabolism abnormalities and amyloid deposition in obese agouti viable yellow (A vy ) mice that overexpress hIAPP in β cells (A vy hIAPP mice), which exhibit overt diabetes. Oral PBA treatment started at 8 weeks of age, when A vy hIAPP mice already presented fasting hyperglycemia, glucose intolerance, and impaired insulin secretion. PBA treatment strongly reduced the severe hyperglycemia observed in obese A vy hIAPP mice in fasting and fed conditions throughout the study. This effect was paralleled by a decrease in hyperinsulinemia. Importantly, PBA treatment reduced the prevalence and the severity of islet amyloid deposition in A vy hIAPP mice. Collectively, these results show that PBA treatment elicits a marked reduction of hyperglycemia and reduces amyloid deposits in obese and diabetic mice, highlighting the potential of chaperones for T2D treatment.

Obesity is frequently associated with metabolic disease. Here, we show that obesity changes the miRNA profile of plasma exosomes in mice, including increases in miR-122 , miR-192 , miR-27a-3p , and miR-27b-3p Importantly, treatment of lean mice with exosomes isolated from obese mice induces glucose intolerance and insulin resistance. Moreover, administration of control exosomes transfected with obesity-associated miRNA mimics strongly induces glucose intolerance in lean mice and results in central obesity and hepatic steatosis. Expression of the candidate target gene Ppara is decreased in white adipose tissue but not in the liver of mimic-treated (MIMIC) mice, and this is accompanied by increased circulating free fatty acids and hypertriglyceridemia. Treatment with a specific siRNA targeting Ppara transfected into exosomes recapitulates the phenotype induced by obesity-associated miRNAs. Importantly, simultaneously reducing free fatty acid plasma levels in MIMIC mice with either the lipolysis inhibitor acipimox or the PPARα agonist fenofibrate partially protects against these metabolic alterations. Overall, our data highlight the central role of obesity-associated exosomal miRNAs in the etiopathogeny of glucose intolerance and dyslipidemia., Competing Interests: The authors declare no conflict of interest.

Mitofusin 2 (MFN2) plays critical roles in both mitochondrial fusion and the establishment of mitochondria-endoplasmic reticulum (ER) interactions. Hypothalamic ER stress has emerged as a causative factor for the development of leptin resistance, but the underlying mechanisms are largely unknown. Here, we show that mitochondria-ER contacts in anorexigenic pro-opiomelanocortin (POMC) neurons in the hypothalamus are decreased in diet-induced obesity. POMC-specific ablation of Mfn2 resulted in loss of mitochondria-ER contacts, defective POMC processing, ER stress-induced leptin resistance, hyperphagia, reduced energy expenditure, and obesity. Pharmacological relieve of hypothalamic ER stress reversed these metabolic alterations. Our data establish MFN2 in POMC neurons as an essential regulator of systemic energy balance by fine-tuning the mitochondrial-ER axis homeostasis and function. This previously unrecognized role for MFN2 argues for a crucial involvement in mediating ER stress-induced leptin resistance., (Copyright © 2013 Elsevier Inc. All rights reserved.)

A new way of intercellular communication has been recently demonstrated, consisting of the controlled release of small vesicles loaded with bioactive factors (proteins, lipids, and nucleic acids chiefly amongst them) to the extracellular compartment. Importantly, these extracellular vesicles (EVs), including microvesicles and exosomes, regulate various physiological processes and, when disturbed, may contribute to the onset and progression of many diseases. Hence, they can be exploited as informative biomarkers to diagnose and monitor pathological conditions, including type 2 diabetes and associated metabolic disease. However, currently available techniques to isolate EVs lack reproducibility, effectiveness, and rapidity and require high amounts of starting samples, limiting their introduction in clinical practice. The objective of this work is to use a simple and easy‐to‐use microfluidic platform for capturing and quantifying a specific subpopulation of EVs from a small volume of plasma. As a proof‐of‐concept, the platform is tested with murine plasma. An analysis of the microRNA (miRNA) content of the isolated EVs is performed, detecting significant differences when comparing lean and obese mice. Thus, the device offers an easy, straightforward system to detect and analyze plasma‐derived EVs in the everyday clinical setting. [ABSTRACT FROM AUTHOR]

Obesity and type 2 diabetes are associated with defects of insulin action in different tissues or alterations in β-cell secretory capacity that may be triggered by environmental challenges, inadequate lifestyle choices, or an underlying genetic predisposition. In addition, recent data shows that obesity may also be caused by perturbations of the gut microbiota, which then affect metabolic function and energy homeostasis in the host. Maintenance of metabolic homeostasis in complex organisms such as mammals requires organismal-level communication, including between the different organs and the gut microbiota. Extracellular vesicles (EVs) have been identified in all domains of life and have emerged as crucial players in inter-organ and inter-kingdom crosstalk. Interestingly, EVs found in edible vegetables or in milk have been shown to influence gut microbiota or tissue function in mammals. Moreover, there is a multidirectional crosstalk mediated by EVs derived from gut microbiota and body organs that has implications for host health. Untangling this complex signaling network may help implement novel therapies for the treatment of metabolic disease. [ABSTRACT FROM AUTHOR]

Obesity and other closely associated diseases, such as metabolic-associated fatty liver disease (MAFLD) and type 2 diabetes, give rise to a common biometric and metabolic phenotype resulting from a different etiopathogenesis. To characterize the first stages of metabolic dysfunction induced by either obesity or hepatic steatosis, we compared two animal models of short-term feeding with either high-fat (HFD) or high-sucrose (SAC) diets. Using transcriptomic, metabolic, and calorimetric analyses, we determined that a short-term HFD leads to obesity and then hepatic steatosis through lipid storage, whereas SAC increases gluconeogenesis and de novo lipogenesis, resulting in hepatic steatosis followed later by obesity. Plasma exosomal miRNA profiles differed between HFD and SAC mice, and the injection of exosomes from HFD or SAC mice reproduced some transcriptomic and metabolic features of the donor mice. Finally, we exploited our data to identify circulating miR-22-3p as a candidate biomarker for MAFLD patient stratification. In conclusion, dietary challenges affecting adipose or hepatic metabolism regulate the abundance of exosomal miRNAs in plasma, which in turn modulate gene expression, helping the organism to adapt. [ABSTRACT FROM AUTHOR]

Most cells release extracellular vesicles (EVs) that can be detected circulating in blood. We and others have shown that the microRNA contents of these vesicles induce transcriptomic changes in acceptor cells, contributing to the adjustment of metabolic homeostasis in response to environmental demands. Here, we explore the potential for modulating obesity- and exercise-derived EV-microRNAs to treat the metabolic dysfunction associated with obesity in mice. Treatment with EV-miRNAs alleviated glucose intolerance and insulin resistance in obese mice to an extent similar to that of high-intensity interval training, although only exercise improved cardiorespiratory fitness and decreased body weight. Mechanistically, EV-miRNAs decreased fatty acid and cholesterol biosynthesis pathways in the liver, reducing hepatic steatosis and increasing insulin sensitivity, resulting in decreased glycemia and triglyceridemia. Our data suggest that manipulation of EV-miRNAs may be a viable strategy to alleviate metabolic dysfunction in obese and diabetic patients who are unable to exercise, although actual physical activity is needed to improve cardiorespiratory fitness. [ABSTRACT FROM AUTHOR]

Obesity is frequently associated with metabolic disease. Here, we show that obesity changes themiRNA profile of plasma exosomes in mice, including increases in miR-122, miR-192, miR-27a-3p, and miR-27b-3p. Importantly, treatment of lean mice with exosomes isolated from obese mice induces glucose intolerance and insulin resistance. Moreover, administration of control exosomes transfected with obesity-associated miRNA mimics strongly induces glucose intolerance in lean mice and results in central obesity and hepatic steatosis. Expression of the candidate target gene Ppara is decreased in white adipose tissue but not in the liver of mimic-treated (MIMIC) mice, and this is accompanied by increased circulating free fatty acids and hypertriglyceridemia. Treatment with a specific siRNA targeting Ppara transfected into exosomes recapitulates the phenotype induced by obesity-associated miRNAs. Importantly, simultaneously reducing free fatty acid plasma levels in MIMIC mice with either the lipolysis inhibitor acipimox or the PPARα agonist fenofibrate partially protects against these metabolic alterations. Overall, our data highlight the central role of obesity-associated exosomal miRNAs in the etiopathogeny of glucose intolerance and dyslipidemia. [ABSTRACT FROM AUTHOR]

Abstract: MicroRNAs (miRNAs) have recently emerged as key regulators of metabolism. However, their potential role in the central regulation of whole-body energy homeostasis is still unknown. In this study we show that the expression of Dicer, an essential endoribonuclease for miRNA maturation, is modulated by nutrient availability and excess in the hypothalamus. Conditional deletion of Dicer in POMC-expressing cells resulted in obesity, characterized by hyperphagia, increased adiposity, hyperleptinemia, defective glucose metabolism and alterations in the pituitary–adrenal axis. The development of the obese phenotype was paralleled by a POMC neuron degenerative process that started around 3 weeks of age. Hypothalamic transcriptomic analysis in presymptomatic POMCDicerKO mice revealed the downregulation of genes implicated in biological pathways associated with classical neurodegenerative disorders, such as MAPK signaling, ubiquitin–proteosome system, autophagy and ribosome biosynthesis. Collectively, our results highlight a key role for miRNAs in POMC neuron survival and the consequent development of neurodegenerative obesity. [Copyright &y& Elsevier]

Diabetes is a group of metabolic diseases characterized by elevated blood glucose levels that drive the development of life-threatening complications. Diabetes results from a situation of insufficient insulin action, either by deficient production of the hormone by the pancreas, or by the development of insulin resistance in peripheral tissues such as liver, muscle, or the adipose depots. Communication between organs is thus central to the maintenance of glucose homoeostasis. Recently, several studies are evidencing that small vesicles called exosomes released by, amongst other, the adipose tissue can regulate gene expression in other tissues, hence modulating interorgan crosstalk. Therefore, exosomes participate in the development of diabetes and its associated complications. Their study holds the potential of providing us with novel biomarkers for the early diagnosis and stratification of patients at risk of developing diabetes, hence allowing the timely implementation of more personalized therapies. On the other hand, the molecular dissection of the pathways initiated by exosomes under situations of metabolic stress could help to gain a deeper knowledge of the pathophysiology of diabetes and its associated metabolic diseases. [ABSTRACT FROM AUTHOR]