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Pancreatic β-cell dysfunction caused by obesity can be associated with alterations in the levels of miRNAs. However, the role of miRNAs in such processes remains elusive. Here, we show that pancreatic islet miR-27a-5p, which is markedly increased in obese mice and impairs insulin secretion, is mainly delivered by visceral adipocyte–derived extracellular vesicles (EVs). Depleting miR-27a-5p significantly improved insulin secretion and glucose intolerance in db / db mice. Supporting the function of EV miR-27a-5p as a key pathogenic factor, intravenous injection of miR-27a-5p–containing EVs showed their distribution in mouse pancreatic islets. Tracing the injected adeno-associated virus (AAV)-miR-27a-5p (AAV-miR-27a) or AAV-FABP4-miR-27a-5p (AAV-FABP4-miR-27a) in visceral fat resulted in upregulating miR-27a-5p in EVs and serum and elicited mouse pancreatic β-cell dysfunction. Mechanistically, miR-27a-5p directly targeted L-type Ca2+ channel subtype CaV1.2 (Cacna1c) and reduced insulin secretion in β-cells. Overexpressing mouse CaV1.2 largely abolished the insulin secretion injury induced by miR-27a-5p. These findings reveal a causative role of EV miR-27a-5p in visceral adipocyte–mediated pancreatic β-cell dysfunction in obesity-associated type 2 diabetes mellitus. Article Highlights: miR-27a-5p expression in the islets is increased in obesity-associated diabetes mouse models. miR-27a-5p overexpression in β-cells impairs β-cell function in vitro and in vivo. Visceral adipocyte–derived extracellular vesicles and their cargo miR-27a-5p lead to β-cell insulin secretion injury and glucose intolerance by targeting L-type Ca2+ channel subtype CaV1.2. Blockage of visceral adipocyte extracellular vesicle miR-27a-5p expression improves β-cell insulin secretion and glucose tolerance in db / db mice. [ABSTRACT FROM AUTHOR]

Maturation of postnatal β-cells is regulated in a cell-autonomous manner, and metabolically stressed β-cells regress to an immature state, ensuring defective β-cell function and the onset of type 2 diabetes. The molecular mechanisms connecting the nutritional transition to β-cell maturation remain largely unknown. Here, we report a mature form of miRNA (miR-203)/ZBTB20/MAFA regulatory axis that mediates the β-cell maturation process. We show that the level of the mature form of miRNA (miR-203) in β-cells changes during the nutritional transition and that miR-203 inhibits β-cell maturation at the neonatal stage and under high-fat diet conditions. Using single-cell RNA sequencing, we demonstrated that miR-203 elevation promoted the transition of immature β-cells into CgBHi endocrine cells while suppressing gene expressions associated with β-cell maturation in a ZBTB20/MAFA-dependent manner. ZBTB20 is an authentic target of miR-203 and transcriptionally upregulates MAFA expression. Manipulating the miR-203/ZBTB20/MAFA axis may therefore offer a novel strategy for boosting functional β-cell numbers to alleviate diabetes. Article Highlights: Nutritional transition from a high-fat diet to carbohydrate-rich diet inhibits expression of the mature form of miRNA (miR-203). Failure to inhibit miR-203 during high-fat diet feeding causes β-cell immaturity and loss of identity. Ablation of miR-203 in β-cells prevents high-fat diet–induced β-cell dysfunction. The miR-203-ZBTB20-MAFA axis mediates β-cell immaturity and is conserved in humans. [ABSTRACT FROM AUTHOR]

Chronic inflammation promotes pancreatic β-cell decompensation to insulin resistance because of local accumulation of supraphysiologic interleukin 1β (IL-1β) levels. However, the underlying molecular mechanisms remain elusive. We show that miR-503-5p is exclusively upregulated in islets from humans with type 2 diabetes and diabetic rodents because of its promoter hypomethylation and increased local IL-1β levels. β-Cell–specific miR-503 transgenic mice display mild or severe diabetes in a time- and expression-dependent manner. By contrast, deletion of the miR-503 cluster protects mice from high-fat diet–induced insulin resistance and glucose intolerance. Mechanistically, miR-503-5p represses c-Jun N-terminal kinase–interacting protein 2 (JIP2) translation to activate mitogen-activated protein kinase signaling cascades, thus inhibiting glucose-stimulated insulin secretion (GSIS) and compensatory β-cell proliferation. In addition, β-cell miR-503-5p is packaged in nanovesicles to dampen insulin signaling transduction in liver and adipose tissues by targeting insulin receptors. Notably, specifically blocking the miR-503 cluster in β-cells effectively remits aging-associated diabetes through recovery of GSIS capacity and insulin sensitivity. Our findings demonstrate that β-cell miR-503-5p is required for the development of insulin resistance and β-cell decompensation, providing a potential therapeutic target against diabetes. Article Highlights: Promoter hypomethylation during natural aging permits miR-503-5p overexpression in islets under inflammation conditions, conserving from rodents to humans. Impaired β-cells release nanovesicular miR-503-5p to accumulate in liver and adipose tissue, leading to their insulin resistance via the miR-503-5p/insulin receptor/phosphorylated AKT axis. Accumulated miR-503-5p in β-cells impairs glucose-stimulated insulin secretion via the JIP2-coordinated mitogen-activated protein kinase signaling cascades. Specific blockage of β-cell miR-503-5p improves β-cell function and glucose tolerance in aging mice. [ABSTRACT FROM AUTHOR]

The accumulation of mitochondria in thermogenic adipose tissue (i.e., brown and beige fat) increases energy expenditure, which can aid in alleviating obesity and metabolic disorders. However, recent studies have shown that knocking out key proteins required to maintain mitochondrial function inhibits the energy expenditure in thermogenic fat, and yet the knockout mice are unexpectedly protected from developing obesity or metabolic disorders when fed a high-fat diet (HFD). In the present study, non-biased sequencing-based screening revealed the importance of YY1 in the transcription of electron transport chain genes and the enhancement of mitochondrial function in thermogenic adipose tissue. Specifically, adipocyte YY1 null (YAKO) mice showed lower energy expenditure and were intolerant to cold stress. Interestingly, YAKO mice showed alleviation of HFD-induced metabolic disorders, which can be attributed to a suppression of adipose tissue inflammation. Metabolomic analysis revealed that blocking YY1 directed glucose metabolism toward lactate, enhanced the uptake of glutamine, and promoted the production of anti-inflammatory spermidine. Conversely, blocking spermidine production in YAKO mice reversed their resistance to HFD-induced disorders. Thus, although blocking adipocyte YY1 impairs the thermogenesis, it promotes spermidine production and alleviates adipose tissue inflammation, therefore leads to an uncoupling of adipose tissue energy expenditure from HFD-induced metabolic disorders., (© 2024 by the American Diabetes Association.)