American Journal of Physiology. Endocrinology and Metabolism

The quality of skeletal muscle is maintained by a balance between protein biosynthesis and degradation. Disruption in this balance results in sarcopenia. However, its underlying mechanisms remain under-investigated. Selenoprotein P (SeP; encoded by Selenop in mice) is a hepatokine that is upregulated in type 2 diabetes and aging and causes signal resistances via reductive stress. We created immobilized muscle atrophy (IMM) model in Selenop knockout (KO) mice. IMM significantly reduced cross-sectional areas and the size of skeletal muscle fibers, which were ameliorated in KO mice...

BACKGROUND AND OBJECTIVE: Insulin's microvascular actions and their relationship to insulin's metabolic actions have not been well-studied in adults with type 1 diabetes mellitus (T1DM). We compared metabolic and selected micro- and macro-vascular responses to insulin by healthy adult control (n=16) and T1DM (n=15) subjects without clinical microvascular disease. DESIGN AND METHODS: We measured insulin's effect on: a) skeletal muscle microvascular perfusion using contrast-enhanced ultrasound (CEU); b) arterial stiffness using carotid-femoral pulse-wave velocity (cfPWV) and radial artery pulse wave analysis (PWA); and c) metabolic insulin sensitivity by the glucose infusion rate (GIR) during a 2-h, 1 mU/min/kg euglycemic-insulin clamp...

Muscle contractile activity stimulates intramuscular recruitment of immune cells including neutrophils emerging to serve as a prerequisite for exerting proper muscular performance, although the underlying mechanisms and their contributions to myokine upregulation remain ill-defined. We previously reported that pharmacological inhibition of CX3CR1, a fractalkine receptor, dampens gnawing-dependent neutrophil recruitment into masseter muscles along with compromising their masticatory activity. By employing a running exercise model, we herein demonstrated that hindlimb muscles require collaborative actions of both CX3CR1- and CXCR2-mediated signals for achieving neutrophil recruitment, upregulation of myokines including interleukin (IL)-6, enhanced GLUT4 translocation, and adequate endurance capability...

Cold acclimation and pharmacological peroxisome proliferator-activated receptor γ (PPARγ) activation have each earlier been shown to recruit brown adipose tissue (BAT) and beige adipocytes thermogenic machinery, enhancing uncoupling protein 1 (UCP1)-mediated thermogenic capacity. We here investigated whether cold acclimation and PPARγ agonism combined have additive effects in inducing brown and beige adipocytes UCP1 content and whether this translates into a higher thermogenic capacity and energy expenditure...

Lactate, which is an end product of glycolysis, has traditionally been considered as a metabolic waste. However, numerous studies have demonstrated that lactate serves metabolic and nonmetabolic functions in physiological processes and multiple diseases. Cancer and pulmonary arterial hypertension have been shown to undergo metabolic reprogramming, which is accompanied by increased lactate production. Metabolic reprogramming and epigenetic modifications have been extensively linked; furthermore, posttranslational modifications of histones caused by metabolites play a vital role in epigenetic alterations...

Succinate is released by skeletal muscle during exercise and activates SUCNR1 /GPR91. Signaling of SUCNR1 is involved in metabolite-sensing paracrine communication in skeletal muscle during exercise. However, the specific cell types responding to succinate and the directionality of communication are unclear. We aim to characterize the expression of SUCNR1 in human skeletal muscle. De novo analysis of transcriptomic datasets demonstrated that SUCNR1 mRNA is expressed in immune, adipose, and liver tissues, but scarce in skeletal muscle...

BACKGROUND: Thrombospondin-1 (TSP1) is a secreted protein minimally expressed in health but increased in disease and age. TSP1 binds to the cell membrane receptor CD47, which itself engages signal regulatory protein α (SIRPα) and the latter creates a checkpoint for immune activation. Individuals with cancer administered checkpoint blocking molecules developed insulin-dependent diabetes. Relevant to this, CD47 blocking antibodies and SIRPα fusion proteins are in clinical trials...

There is a debate on whether lipid-mediated insulin resistance derives from an increased or decreased capacity of muscle to oxidize fats. Here we examine the involvement of muscle fiber composition in the metabolic responses to a 3-day fast (starvation, which results in increases in plasma lipids and insulin resistance) in two groups of healthy young subjects: 1, area occupied by type I fibers = 61.0 ± 11.8%; 2, type I area = 36.0 ± 4.9% (P<0.001). Muscle biopsies and intravenous glucose tolerance tests were performed after an overnight fast and after starvation...

BACKGROUND: Many cells adapt to hyperosmolal conditions by upregulation of organic osmolytes to maintain cell function and integrity. Glycerophosphocholine (GPC), a recognised osmolyte in renal medullary cells, is the major phosphodiester (PDE) in human skeletal muscle, wherefore we hypothesized muscular GPC to be associated with surrogate parameters of fluid status and osmolality in healthy humans. OBJECTIVES: To investigate the relationship of muscular GPC with surrogate parameters of body fluid status and osmolality...

Metabolic and molecular interactions between branched chain amino acid (BCAA) and lipid metabolism are evident in insulin resistant tissues. However, it remains unclear whether insulin resistance is a prerequisite for these relationships and whether BCAAs or their metabolic intermediates can modulate hepatic lipid oxidation and synthesis. We hypothesized that BCAAs can alter hepatic oxidative function and de novo lipogenesis, independent of them being anaplerotic substrates for the mitochondria. Mice (C57BL/6NJ) were reared on a low-fat (LF), LF diet plus 1...

In pediatric population with diabetes and obesity, insulin resistance (HOMA-IR) has been associated with worsening vascular outcomes, however, the cumulative role of HOMA-IR, hyperglycemia, and hyperinsulinemia on repeatedly measured vascular outcomes in asymptomatic youth is unknown. We examined the longitudinal associations of fasting glucose, insulin, and HOMA-IR with carotid-femoral pulse wave velocity (cfPWV) and carotid intima-media thickness (cIMT). From the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort, UK 1779, 15-year-old participants were followed-up for 9 years...

Obesity is one of the leading non-communicable diseases in the world. Despite intense efforts to develop strategies to prevent and treat obesity, its prevalence continues to rise worldwide. A recent study has shown that the tricarboxylic acid intermediate succinate increases body energy expenditure by promoting brown adipose tissue thermogenesis through the activation of uncoupling protein-1; this has generated interest surrounding its potential usefulness as an approach to treat obesity. It is currently unknown how succinate impacts brown adipose tissue protein expression, and how exogenous succinate impacts body mass reduction promoted by a drug approved to treat human obesity, the glucagon-like-1 receptor agonist, liraglutide...

Skeletal muscle atrophy is often found in patients with type 2 diabetes mellitus (T2DM) which is characterized with insulin resistance. As the largest tissue in the body, skeletal muscle plays important roles in insulin resistance. Advanced glycation end products (AGEs) are representative toxic metabolites and associated with multiple pathophysiologic changes of T2DM. In this study, we investigated whether AGEs could exacerbate skeletal muscle atrophy and its related insulin resistance. Mice were exposed to AGEs...

Treatment with tyrosine kinase inhibitors (TKIs), especially nilotinib, often results in hyperglycemia, which may further increase cardiovascular disease risk in patients with chronic myeloid leukemia (CML). The mechanism underlying the TKI-induced glucose deregulation is not clear. TKIs are suggested to affect insulin secretion but also insulin sensitivity of peripheral tissue has been proposed to play a role in the pathogenesis of TKI-induced hyperglycemia. Here, we aimed to assess whether skeletal muscle glucose uptake and insulin responses are altered in non-diabetic CML patients receiving TKI treatment...

Delta-6 desaturase (D6D), encoded by the Fads2 gene, catalyzes the first step in the conversion of alpha-linolenic acid to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The ablation of D6D in whole-body Fads2-/- knockout (KO) mice results in an inability to endogenously produce EPA and DHA. Evidence supports a beneficial role for EPA and DHA on insulin-stimulated glucose disposal in skeletal muscle in the context of a metabolic challenge; however, it is unknown how low EPA and DHA levels impact skeletal muscle fatty acid composition and insulin signaling in a healthy context...

The autonomic nervous system regulates pancreatic function. Islet capillaries are essential for the extension of axonal projections into islets, and both of these structures are important for appropriate islet hormone secretion. Because beta cells provide important paracrine cues for islet glucagon secretion and neurovascular development, we postulated that beta cell loss in type 1 diabetes (T1D) would lead to a decline in intra-islet capillaries and reduction of islet innervation, possibly contributing to abnormal glucagon secretion...

Insulin secretion from β-cells is tightly regulated by local signaling from preproglucagon (Gcg) products from neighboring α-cells. Physiological paracrine signaling within the microenvironment of the β-cell is altered after metabolic stress, such as high-fat diet or the β-cell toxin, streptozotocin. Here, we examined the role and source of Gcg peptides in β-cell function and in response to STZ-induced hyperglycemia. We utilized whole body Gcg null (GcgNull ) mice and mice with Gcg expression either specifically within the pancreas (GcgΔ Panc ) or the intestine (GcgΔ Intest )...

Kisspeptin and gamma amino butyric acid (GABA), synthesized in the central nervous system, are critical for reproduction. Both are also expressed in peripheral organs/tissues critical to metabolic control (liver/pancreas/adipose). Many kisspeptin neurons coexpress GABAB receptors (GABABR) and GABA controls kisspeptin expression and secretion. We developed a unique mouse lacking GABABR exclusively from kisspeptin cells/neurons (Kiss1-GABAB1KO) to evaluate the impact on metabolism/reproduction. We confirmed selective deletion of GABABR from Kiss1 cells in the anteroventral periventricular nucleus/periventricular nucleus continuum (AVPV/PeN; immunofluorescence and PCR) and arcuate nucleus (ARC), medial amygdala (MeA), pituitary, liver and testes (PCR)...

It has been proposed that brain glucagon action inhibits glucagon stimulated hepatic glucose production (HGP), which may explain, at least in part, why glucagon's effect on HGP is transient. Pharmacologic off-target effects of glucagon in the brain may have been responsible for previously observed effects, however. Therefore, the aim of this study was to determine if central glucagon action plays a physiologic role in the regulation of HGP. Insulin was maintained at baseline while glucagon was either infused into the carotid and vertebral arteries or into a peripheral (leg) vein at rates designed to increase glucagon in the head in one group, while keeping glucagon at the liver matched between groups...

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. Dysregulation in hepatic lipid metabolism, including increased fatty acid uptake and de novo lipogenesis (DNL), is a hallmark of NAFLD. Here, we investigated dual inhibition of the fatty acid transporter fatty acid translocase (FAT/CD36), and acetyl-CoA carboxylase (ACC), the rate-limiting enzyme in DNL, for the treatment of NAFLD in mice. Mice with hepatic CD36 deletion (Cd36LKO ) and wildtype littermates were fed a high fat diet for 12 weeks and treated daily with either oral administration of an ACC inhibitor (GS-834356, Gilead Sciences, ACCi) or vehicle for 8 weeks...