Summary Mitochondria are known to be functional organelles, but their role as a signaling unit is increasingly being appreciated. The identification of a short open reading frame (sORF) in the mitochondrial DNA (mtDNA) that encodes a signaling peptide, humanin, suggests the possible existence of additional sORFs in the mtDNA. Here we report a sORF within the mitochondrial 12S rRNA encoding a 16 amino acid peptide named MOTS-c (mitochondrial open-reading-frame of the twelve S rRNA -c) that regulates insulin sensitivity and metabolic homeostasis. Its primary target organ appears to be the skeletal muscle and its cellular actions inhibit the folate cycle and its tethered de novo purine biosynthesis, leading to AMPK activation. MOTS-c treatment in mice prevented age-dependent and high-fat diet-induced insulin resistance, as well as diet-induced obesity. These results suggest that mitochondria may actively regulate metabolic homeostasis at the cellular and organismal level via peptides encoded within their genome.

Background-Low plasma high-density lipoprotein (HDL) is associated with elevated cardiovascular risk and aspects of the metabolic syndrome. We hypothesized that HDL modulates glucose metabolism via elevation of plasma insulin and through activation of the key metabolic regulatory enzyme, AMP-activated protein kinase, in skeletal muscle. Methods and Results-Thirteen patients with type 2 diabetes mellitus received both intravenous reconstituted HDL (rHDL: 80 mg/kg over 4 hours) and placebo on separate days in a double-blind, placebo-controlled crossover study. A greater fall in plasma glucose from baseline occurred during rHDL than during placebo (at 4 hours rHDLϭϪ2.6Ϯ0.4; placeboϭϪ2.1Ϯ0.3mmol/L; Pϭ0.018). rHDL increased plasma insulin (at 4 hours rHDLϭ3.4Ϯ10.0; placeboϭ Ϫ19.2Ϯ7.4 pmol/L; Pϭ0.034) and also the homeostasis model assessment ␤-cell function index (at 4 hours rHDLϭ18.9Ϯ5.9; placeboϭ8.6Ϯ4.4%; Pϭ0.025). Acetyl-CoA carboxylase ␤ phosphorylation in skeletal muscle biopsies was increased by 1.7Ϯ0.3-fold after rHDL, indicating activation of the AMP-activated protein kinase pathway. Both HDL and apolipoprotein AI increased glucose uptake (by 177Ϯ12% and 144Ϯ18%, respectively; PϽ0.05 for both) in primary human skeletal muscle cell cultures established from patients with type 2 diabetes mellitus (nϭ5). The mechanism is demonstrated to include stimulation of the ATP-binding cassette transporter A1 with subsequent activation of the calcium/calmodulin-dependent protein kinase kinase and the AMP-activated protein kinase pathway. Conclusions-rHDL reduced plasma glucose in patients with type 2 diabetes mellitus by increasing plasma insulin and activating AMP-activated protein kinase in skeletal muscle. These findings suggest a role for HDL-raising therapies beyond atherosclerosis to address type 2 diabetes mellitus. Key Words: glucose Ⅲ insulin Ⅲ lipoproteins Ⅲ metabolism Ⅲ muscles H igh-density lipoprotein (HDL) is associated with protection from adverse cardiovascular outcomes in large epidemiological trials. 1 Type 2 diabetes mellitus and the cluster of pathologies including glucose intolerance/insulin resistance, obesity, and high plasma triglycerides that constitute the metabolic syndrome are associated with low and dysfunctional HDL. 2,3 In contrast, aerobically trained individuals have high HDL and display enhanced glucose tolerance. 4 Although the mechanisms linking low HDL to atherosclerosis are well characterized, the links between low HDL and disordered energy metabolism remain relatively unexplored. Given the high and escalating prevalence of type 2 diabetes mellitus, obesity, and the metabolic syndrome and the associated marked elevation in cardiovascular morbidity and mortality, this is an important area of investigation. Clinical Perspective p 2111Recent cell-based studies suggest that HDL may modulate plasma glucose through both insulin-dependent 5,6 and -independent mechanisms. 7 The ATP-binding cassette transporter A1 (ABCA1) has been shown to modulate insulin secretion, 6 and HDL can reverse ...

OBJECTIVE-Activation of the receptor for advanced glycation end products (RAGE) in diabetic vasculature is considered to be a key mediator of atherogenesis. This study examines the effects of deletion of RAGE on the development of atherosclerosis in the diabetic apoE Ϫ/Ϫ model of accelerated atherosclerosis. RESEARCH DESIGN AND METHODS-ApoEϪ/Ϫ and RAGE Ϫ/Ϫ / apoE Ϫ/Ϫ double knockout mice were rendered diabetic with streptozotocin and followed for 20 weeks, at which time plaque accumulation was assessed by en face analysis. RESULTS-Although diabetic apoEϪ/Ϫ mice showed increased plaque accumulation (14.9 Ϯ 1.7%), diabetic RAGE Ϫ/Ϫ /apoE Ϫ/Ϫ mice had significantly reduced atherosclerotic plaque area (4.9 Ϯ 0.4%) to levels not significantly different from control apoE Ϫ/Ϫ mice (4.3 Ϯ 0.4%). These beneficial effects on the vasculature were associated with attenuation of leukocyte recruitment; decreased expression of proinflammatory mediators, including the nuclear factor-B subunit p65, VCAM-1, and MCP-1; and reduced oxidative stress, as reflected by staining for nitrotyrosine and reduced expression of various NADPH oxidase subunits, gp91phox, p47phox, and rac-1. Both RAGE and RAGE ligands, including S100A8/A9, high mobility group box 1 (HMGB1), and the advanced glycation end product (AGE) carboxymethyllysine were increased in plaques from diabetic apoE Ϫ/Ϫ mice. Furthermore, the accumulation of AGEs and other ligands to RAGE was reduced in diabetic RAGECONCLUSIONS-This study provides evidence for RAGE playing a central role in the development of accelerated atherosclerosis associated with diabetes. These findings emphasize the potential utility of strategies targeting RAGE activation in the prevention and treatment of diabetic macrovascular complications. Diabetes 57:2461-2469, 2008 T he receptor for advanced glycation end products (RAGE) is a multiligand cell surface molecule belonging to the immunoglobulin superfamily (1). It is expressed as full-length, N-truncated, and C-truncated isoforms, generated in humans by alternative splicing (2). Activation of the full-length RAGE receptor has been implicated in a range of chronic diseases, including various diabetic complications and atherosclerosis (1). In particular, studies in RAGE Ϫ/Ϫ mice that carry the dominant-negative form of the receptor (2-6) and in RAGE-overexpressing mice (7) have confirmed an important role of RAGE activation in the development of diabetic nephropathy, neuropathy, and impaired angiogenesis. RAGE activation has also been implicated in the acceleration of atherosclerotic lesion formation as well as in the maintenance of proinflammatory and prothrombotic mechanisms, characteristic of diabetes-accelerated atherosclerosis (8,9). RAGE also represents an important mediator of oxidative stress in diabetes. Activation of RAGE in vitro leads to increased NADPH oxidase expression, mitochondrial oxidase activity, and downregulation of endogenous antioxidant activity (10,11). RAGE Ϫ/Ϫ mice have a suppression of neointimal proliferation after externally...

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Impaired estrogen receptor α(ERα) action promotes obesity and metabolic dysfunction in humans and mice; however, the mechanisms underlying these phenotypes remain unknown. Considering that skeletal muscle is a primary tissue responsible for glucose disposal and oxidative metabolism, we established that reduced ERαexpression in muscle is associated with glucose intolerance and adiposity in women and female mice. To test this relationship, we generated muscle-specific ERαknockout (MERKO) mice. Impaired glucose homeostasis and increased adiposity were paralleled by diminished muscle oxidative metabolism and bioactive lipid accumulation in MERKO mice. Aberrant mitochondrial morphology, overproduction of reactive oxygen species, and impairment in basal and stress-induced mitochondrial fission dynamics, driven by imbalanced protein kinase A–regulator of calcineurin 1–calcineurin signaling through dynamin-related protein 1, tracked with reduced oxidative metabolism in MERKO muscle. Although muscle mitochondrial DNA (mtDNA) abundance was similar between the genotypes, ERαdeficiency diminished mtDNA turnover by a balanced reduction in mtDNA replication and degradation. Our findings indicate the retention of dysfunctional mitochondria in MERKO muscle and implicate ERαin the preservation of mitochondrial health and insulin sensitivity as a defense against metabolic disease in women.