Background and Aims NAFLD, characterized by aberrant triglyceride accumulation in liver, affects the metabolic remodeling of hepatic and nonhepatic tissues by secreting altered hepatokines. Small ubiquitin‐related modifier (SUMO)–specific protease 2 (SENP2) is responsible for de‐SUMOylation of target protein, with broad effects on cell growth, signal transduction, and developmental processes. However, the role of SENP2 in hepatic metabolism remains unclear. Approach and Results We found that SENP2 was the most dramatically increased SENP in the fatty liver and that its level was modulated by fed/fasted conditions. To define the role of hepatic SENP2 in metabolic regulation, we generated liver‐specific SENP2 knockout (Senp2‐LKO) mice. Senp2‐LKO mice exhibited resistance to high‐fat diet–induced hepatic steatosis and obesity. RNA‐sequencing analysis showed that Senp2 deficiency up‐regulated genes involved in fatty acid oxidation and down‐regulated genes in lipogenesis in the liver. Additionally, ablation of hepatic SENP2 activated thermogenesis of adipose tissues. Improved energy homeostasis of both the liver and adipose tissues by SENP2 disruption prompted us to detect the hepatokines, with FGF21 identified as a key factor markedly elevated in Senp2‐LKO mice that maintained metabolic homeostasis. Loss of FGF21 obviously reversed the positive effects of SENP2 deficiency on metabolism. Mechanistically, by screening transcriptional factors of FGF21, peroxisome proliferator–activated receptor alpha (PPARα) was defined as the mediator for SENP2 and FGF21. SENP2 interacted with PPARα and deSUMOylated it, thereby promoting ubiquitylation and subsequent degradation of PPARα, which in turn inhibited FGF21 expression and fatty acid oxidation. Consistently, SENP2 overexpression in liver facilitated development of metabolic disorders. Conclusions Our finding demonstrated a key role of hepatic SENP2 in governing metabolic balance by regulating liver–adipose tissue crosstalk, linking the SUMOylation process to metabolic regulation.

Brown and beige adipocytes dissipate energy in a non-shivering thermogenesis manner, exerting beneficial effects on metabolic homeostasis. CHCHD10 is a nuclear-encoded mitochondrial protein involved in cristae organization; however, its role in thermogenic adipocytes remains unknown. Herein, we identify CHCHD10 as a novel regulator for adipocyte thermogenesis. CHCHD10 is dramatically upregulated during thermogenic adipocytes activation by PPARγ-PGC1α, and positively correlated with UCP1 expression in the adipose tissues from human and mice. We generate adipocyte-specific Chchd10 knockout mice (Chchd10-AKO) and find that depleting CHCHD10 leads to impaired UCP1-dependent thermogenesis and energy expenditure in the fasting state, with no effect in fed state. Lipolysis in adipocytes is disrupted by CHCHD10 deficiency, while augmented lipolysis via ATGL overexpression recovers adipocyte thermogenesis in Chchd10-AKO mice. Consistently, overexpression of Chchd10 activates thermogenic adipocytes. Mechanistically, CHCHD10 deficiency results in the disorganization of mitochondrial cristae, leading to impairment of oxidative phosphorylation complex assembly in mitochondria, which in turn inhibits ATP generation. Decreased ATP results in downregulation of lipolysis by reducing nascent protein synthesis of ATGL, thereby suppressing adipocyte thermogenesis. As a result, Chchd10-AKO mice are prone to develop high-fat diet-induced metabolic disorders. Together, our findings reveal essential role of CHCHD10 in regulating lipolysis and thermogenic program in adipocytes.

Background and Objective: microRNAs (miRNAs) are short non-coding RNAs that have emerged to be the novel post-transcriptional regulators of gene expression, contributing to the development of metabolic diseases such as diabetes. Also, new and more precise high-throughput analytical tools have made it possible to study miRNAs' complex causative roles and targets. Here, we summarise the available evidence for the roles of miRNAs in the endocrine pancreas regulating fundamental cellular processes in beta-cells and the pathology of diabetes.Methods: We searched PubMed for research conducted and published before June 2022 using classical Boolean expressions. Only manuscripts written in English were considered.Key Content and Findings: Numerous miRNAs in the endocrine pancreas have been reported to regulate the fundamental cellular processes in beta-cells, such as proliferation, differentiation, apoptosis, and insulin biosynthesis and secretion by post-transcriptionally repressing their targets, as well as contributing to the pathology of diabetes. Also, many miRNAs, as molecular cargo of exosomes-mediate the crosstalk between the pancreas and other peripheral organs, unravelling new pathophysiological mechanisms related to the onset and worsening of diabetes.Conclusions: This review summarised the existing evidence of the complex network of miRNAs regulating the endocrine pancreas function and pathology of diabetes, providing the theoretical base for a future scientific study revealing the mechanism of diabetes and facilitating the discovery of new therapeutical targets in clinical practise.