Myokines:metabolic regulation in obesity and type 2 diabetes

Skeletal muscle plays a vital role in the regulation of systemic metabolism,partly through its secretion of endocrine factors which are collectively known as myokines.Altered myokine levels are associated with metabolic diseases,such as type 2 diabetes(T2D).The significance of interorgan crosstalk,particularly through myokines,has emerged as a fundamental aspect of nutrient and energy homeostasis.However,a comprehensive understanding of myokine biology in the setting of obesity and T2D remains a major challenge.In this review,we discuss the regulation and biological functions of key myokines that have been extensively studied during the past two decades,namely interleukin 6(IL-6),irisin,myostatin(MSTN),growth differentiation factor 11(GDF11),fibroblast growth factor 21(FGF21),apelin,brain-derived neurotrophic factor(BDNF),meteorin-like(Metrnl),secreted protein acidic and rich in cysteine(SPARC),β-aminoisobutyric acid(BAIBA),Musclin,and Dickkopf 3(Dkk3).Related to these,we detail the role of exercise in myokine expression and secretion together with their contributions to metabolic physiology and disease.Despite significant advancements in myokine research,many myokines remain challenging to measure accurately and investigate thoroughly.Hence,new research techniques and detection methods should be developed and rigorously tested.Therefore,developing a comprehensive perspective on myokine biology is crucial,as this will likely offer new insights into the pathophysiological mechanisms underlying obesity and T2D and may reveal novel targets for therapeutic interventions.

Neural innervation in adipose tissue, gut, pancreas, and liver

Efficient communication between the brain and peripheral organs is indispensable for regulating physiological function and maintaining energy homeostasis. The peripheral nervous system (PNS) in vertebrates, consisting of the autonomic and somatic nervous systems, bridges the peripheral organs and the central nervous system (CNS). Metabolic signals are processed by both vagal sensory nerves and somatosensory nerves. The CNS receives sensory inputs via ascending nerves, serves as the coordination and integration center, and subsequently controls internal organs and glands via descending nerves. The autonomic nervous system consists of sympathetic and parasympathetic branches that project peripheral nerves into various anatomical locations to regulate the energy balance. Sympathetic and parasympathetic nerves typically control the reflexive and involuntary functions in organs. In this review article, we outline the innervation of adipose tissue, gut, pancreas, and liver, to illustrate the neurobiological basis of central-peripheral interactions. We emphasize the importance of understanding the functional atlas of neural control of energy metabolism, and more importantly, provide potential avenues for further research in this area.

An integrative profiling of metabolome and transcriptome in the plasma and skeletal muscle following an exercise intervention in diet-induced obese mice

Exercise intervention at the early stage of type 2 diabetes mellitus(T2DM)can aid in the maintenance of blood glucose homeostasis and prevent the development of macrovascular and microvascular complications.However,the exercise-regulated pathways that prevent the development of T2DM remain largely unclear.In this study,two forms of exercise intervention,treadmill training and voluntary wheel running,were conducted for high-fat diet(HFD)-induced obese mice.We observed that both forms of exercise intervention alleviated HFD-induced insulin resistance and glucose intolerance.Skeletal muscle is recognized as the primary site for postprandial glucose uptake and for responsive alteration beyond exercise training.Metabolomic profiling of the plasma and skeletal muscle in Chow,HFD,and HFD-exercise groups revealed robust alterations in metabolic pathways by exercise intervention in both cases.Overlapping analysis identified nine metabolites,including beta-alanine,leucine,valine,and tryptophan,which were reversed by exercise treatment in both the plasma and skeletal muscle.Transcriptomic analysis of gene expression profiles in the skeletal muscle revealed several key pathways involved in the beneficial effects of exercise on metabolic homeostasis.In addition,integrative transcriptomic and metabolomic analyses uncovered strong correlations between the concentrations of bioactive metabolites and the expression levels of genes involved in energy metabolism,insulin sensitivity,and immune response in the skeletal muscle.This work established two models of exercise intervention in obese mice and provided mechanistic insights into the beneficial effects of exercise intervention on systemic energy homeostasis.

The SWI/SNF chromatin-remodeling factors BAF60a, b, and c in nutrient signaling and metabolic control

Metabolic syndrome has become a global epidemic that adversely affects human health. Both genetic and environmental factors contribute to the pathogenesis of metabolic disorders; however, the mechanisms that integrate these cues to regulate metabolic physiology and the development of metabolic disorders remain incompletely defined. Emerging evidence suggests that SWlISNF chromatin.remodeling complexes are critical for directing metabolic reprogramming and adaptation in response to nutritional and other physiological sigrials. The ATP-dependent SWl/SNF ing complexes comprise up to 11 subunits, among which the BAF60 subunit serves as a key link between the core complexes and specific transcriptional factors. The BAF60 subunit has three members, BAF60a, b, and c. The distinct tissue distribution patterns and regulatory mechanisms of BAF60 proteins confer each isoform with specialized functions in different m^abolic cell types. In this review, we summarize the emerging roles and mechanisms of BAF60 proteins in the regulation of nutrient sensing and energy metabolism under physiological and disease conditions.

Transcriptional control of pancreaticβ-cell identity and plasticity during the pathogenesis of type 2 diabetes

Type 2 diabetes(T2D)is caused by insulin resistance and insufficient insulin secretion.Evidence has increasingly indicated that pancreaticβ-cell dysfunction is the primary determinant of T2D disease progression and remission.High plasticity is an important feature of pancreaticβ-cells.During T2D development,pancreaticβ-cells undergo dynamic adaptation.Althoughβ-cell death/apoptosis in later-stage T2D is the major cause ofβ-cell dysfunction,recent studies have revealed thatβ-cell dedifferentiation and reprogramming,which play critical roles inβ-cell functional regulation in the early and middle T2D progression stages,are characterized by(i)a loss of matureβ-cell-enriched genes;(ii)dedifferentiation to a progenitor-like state;and(iii)transdifferentiation into other cell types.The roles of transcription factors(TFs)in the establishment and maintenance ofβ-cell identity during pancreatic development have been extensively studied.Here,we summarize the roles and underlying mechanisms of TFs in the maintenance ofβ-cell identity under physiological and type 2 diabetic conditions.Several feasible approaches for restoring islet functions are also discussed.A better understanding of the transcriptional control ofβ-cell identity and plasticity will pave the way for developing more effective strategies,such asβ-cell regeneration therapy,to treat T2D and associated metabolic disorders.

Intermittent protein restriction protects isletβcells and improves glucose homeostasis in diabetic mice

Diabetes is caused by the interplay between genetics and environmental factors, tightly linked to lifestyle and dietary patterns. In this study, we explored the effectiveness of intermittent protein restriction(IPR)in diabetes control. IPR drastically reduced hyperglycemia in both streptozotocin-treated and leptin receptor-deficient db/db mouse models. IPR improved the number, proliferation, and function of β cells in pancreatic islets. IPR reduced glucose production in the liver and elevated insulin signaling in the skeletal muscle. IPR elevated serum level of FGF21, and deletion of the Fgf21 gene in the liver abrogated the hypoglycemic effect of IPR without affecting β cells. IPR caused less lipid accumulation and damage in the liver than that caused by continuous protein restriction in streptozotocin-treated mice. Single-cell RNA sequencing using mouse islets revealed that IPR reversed diabetes-associated β cell reduction and immune cell accumulation. As IPR is not based on calorie restriction and is highly effective in glycemic control and β cell protection, it has promising translational potential in the future.

Comments on‘Dietary intervention preservesβcell function in mice through CTCF-mediated transcriptional reprogramming’

Type 2 diabetes(T2D)has become a common chronic disease worldwide.Pancreaticβcell dysfunction,together with insulin resistance,is among the main causes for the pathogenesis of T2D.However,the dynamic changes in the number and function ofβcells and the molecular mechanism of irreversible damage in the pathogenesis of T2D are still unclear.A thorough analysis of the mechanism underlyingβcell dysfunction will provide a theoretical basis and molecular targets for the development of new and more effective individualized therapies for diabetes.

β-cell dynamics in type 2 diabetes and in dietary and exercise interventions

Pancreaticβ-cell dysfunction and insulin resistance are two of the major causes of type 2 diabetes(T2D).Recent clinical and experimental studies have suggested that the functional capacity ofβ-cells,particularly in the first phase of insulin secretion,is a primary contributor to the progression of T2D and its associated complications.Pancreaticβ-cells undergo dynamic compensation and decompensation processes during the development of T2D,in which metabolic stresses such as endoplasmic reticulum stress,oxidative stress,and inflammatory signals are key regulators ofβ-cell dynamics.Dietary and exercise interventions have been shown to be effective approaches for the treatment of obesity and T2D,especially in the early stages.Whilst the targeted tissues and underlying mechanisms of dietary and exercise interventions remain somewhat vague,accumulating evidence has implicated the improvement ofβ-cell functional capacity.In this review,we summarize recent advances in the understanding of the dynamic adaptations ofβ-cell function in T2D progression and clarify the effects and mechanisms of dietary and exercise interventions onβ-cell dysfunction in T2D.This review provides molecular insights into the therapeutic effects of dietary and exercise interventions on T2D,and more importantly,it paves the way for future research on the related underlying mechanisms for developing precision prevention and treatment of T2D.