Natriuretic Peptides/cGMP/cGMP-Dependent Protein Kinase Cascades Promote Muscle Mitochondrial Biogenesis and Prevent Obesity

• Published in: Diabetes (New York, N.Y.) Vol. 58; no. 12; pp. 2880 - 2892
• Main Authors: Miyashita, Kazutoshi, Itoh, Hiroshi, Tsujimoto, Hirokazu, Tamura, Naohisa, Fukunaga, Yasutomo, Sone, Masakatsu, Yamahara, Kenichi, Taura, Daisuke, Inuzuka, Megumi, Sonoyama, Takuhiro, Nakao, Kazuwa
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.12.2009
• Subjects: Animals; Biological and medical sciences; Biosynthesis; Blood Glucose - metabolism; Body fat; Cells, Cultured; Cyclic GMP - metabolism; Diabetes; Diabetes. Impaired glucose tolerance; Dietary Fats - administration & dosage; Dietary Fats - adverse effects; Dietary Fats - metabolism; Down-Regulation; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fatty acids; Genetic Engineering; Glucose; Glucose Intolerance - etiology; Glucose Intolerance - metabolism; Heart failure; Hormones; Insulin Resistance; Kinases; Lipid Peroxidation; Lipids; Medical sciences; Metabolic diseases; Metabolic syndrome; Mice; Mice, Knockout; Mitochondria - metabolism; Molecular Sequence Data; Muscle Cells - metabolism; Muscle, Skeletal - metabolism; Musculoskeletal system; Natriuretic Peptide, Brain - metabolism; Natriuretic Peptides - metabolism; Obesity; Obesity - etiology; Obesity - metabolism; Obesity - prevention & control; Original; Oxidation; Oxygen Consumption; Peptides; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Plasma; PPAR delta - metabolism; PPAR gamma - metabolism; Protein Kinases - metabolism; Proteins; Receptors, Atrial Natriuretic Factor - metabolism; Research design; Signal transduction; Trans-Activators - metabolism; Transcription Factors; Transgenic animals; Up-Regulation; Endocrinopathy; Obesity; Mitochondria; Peptides; Enzyme; Transferases; Diabetes mellitus; Non-specific serine/threonine protein kinase; Nutrition disorder; 3',5'-GMP; Muscle; Nutritional status
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db09-0393

Natriuretic Peptides/cGMP/cGMP-Dependent Protein Kinase Cascades Promote Muscle Mitochondrial Biogenesis and Prevent Obesity Kazutoshi Miyashita 1 , Hiroshi Itoh 1 , Hirokazu Tsujimoto 2 , Naohisa Tamura 2 , Yasutomo Fukunaga 2 , Masakatsu Sone 2 , Kenichi Yamahara 2 , Daisuke Taura 2 , Megumi Inuzuka 2 , Takuhiro Sonoyama 2 and Kazuwa Nakao 2 1 Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan; 2 Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan. Corresponding author: Hiroshi Itoh, hrith{at}sc.itc.keio.ac.jp . Abstract OBJECTIVE Natriuretic peptides (NPs) have been characterized as vascular hormones that regulate vascular tone via guanylyl cyclase (GC), cyclic GMP (cGMP), and cGMP-dependent protein kinase (cGK). Recent clinical studies have shown that plasma NP levels were lower in subjects with the metabolic syndrome. The present study was conducted to elucidate the roles for NP/cGK cascades in energy metabolism. RESEARCH DESIGN AND METHODS We used three types of genetically engineered mice: brain NP (BNP) transgenic (BNP-Tg), cGK-Tg, and guanylyl cyclase-A (GCA) heterozygous knockout (GCA +/− ) mice and analyzed the metabolic consequences of chronic activation of NP/cGK cascades in vivo. We also examined the effect of NPs in cultured myocytes. RESULTS BNP-Tg mice fed on high-fat diet were protected against diet-induced obesity and insulin resistance, and cGK-Tg mice had reduced body weight even on standard diet; surprisingly, giant mitochondria were densely packed in the skeletal muscle. Both mice showed an increase in muscle mitochondrial content and fat oxidation through upregulation of peroxisome proliferator–activated receptor (PPAR)-γ coactivator (PGC)-1α and PPARδ. The functional NP receptors, GCA and guanylyl cyclase-B, were downregulated by feeding a high-fat diet, while GCA +/− mice showed increases in body weight and glucose intolerance when fed a high-fat diet. NPs directly increased the expression of PGC-1α and PPARδ and mitochondrial content in cultured myocytes. CONCLUSIONS The findings together suggest that NP/cGK cascades can promote muscle mitochondrial biogenesis and fat oxidation, as to prevent obesity and glucose intolerance. The vascular hormone, NP, would contribute to coordinated regulation of oxygen supply and consumption. Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. See accompanying commentary, p. 2726 . . Received March 15, 2009. Accepted July 28, 2009. © 2009 American Diabetes Association