Natriuretic peptides/cGMP/cGMP-dependent protein kinase cascades promote muscle mitochondrial biogenesis and prevent obesity.
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.


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)-gamma coactivator (PGC)-1alpha and PPARdelta. 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-1alpha and PPARdelta 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.
Miyashita
Kazutoshi
K
Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
Itoh
Hiroshi
H
Tsujimoto
Hirokazu
H
Tamura
Naohisa
N
Fukunaga
Yasutomo
Y
Sone
Masakatsu
M
Yamahara
Kenichi
K
Taura
Daisuke
D
Inuzuka
Megumi
M
Sonoyama
Takuhiro
T
Nakao
Kazuwa
K
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism*; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism*; D015536:Down-Regulation; D005818:Genetic Engineering; D018149:Glucose Intolerance / Q000209:etiology / Q000378:metabolism*; D007333:Insulin Resistance; D015227:Lipid Peroxidation; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D008969:Molecular Sequence Data; D032342:Muscle Cells / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D045265:Natriuretic Peptides / Q000378:metabolism*; D009765:Obesity / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D010101:Oxygen Consumption; D047494:PPAR delta / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011494:Protein Kinases / Q000378:metabolism*; D017461:Receptors, Atrial Natriuretic Factor / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D015854:Up-Regulation
D001786:Blood Glucose; D004041:Dietary Fats; D045265:Natriuretic Peptides; D047494:PPAR delta; D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D020097:Natriuretic Peptide, Brain; D011494:Protein Kinases; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A; D006152:Cyclic GMP
Biochem Biophys Res Commun. 1999 Apr 2;257(1):79-83
10092513
Cell Metab. 2005 Jun;1(6):361-70
16054085
FASEB J. 2004 May;18(7):908-10
15033935
Science. 2002 Aug 2;297(5582):843-5
12161655
Nature. 1995 Nov 2;378(6552):65-8
7477288
Diabetes. 2000 May;49(5):684-7
10905473
Expert Opin Investig Drugs. 2004 Jun;13(6):643-52
15174950
Biochem Biophys Res Commun. 2008 Mar 21;367(4):840-5
18194668
Trends Endocrinol Metab. 2008 May-Jun;19(4):130-7
18337116
Am J Physiol Regul Integr Comp Physiol. 2007 May;292(5):R1851-61
17303681
J Clin Invest. 1994 May;93(5):1911-21
8182124
Endocrinology. 2001 Dec;142(12):5220-5
11713218
Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19926-31
19066218
Circulation. 2007 Mar 20;115(11):1345-53
17339551
Nat Med. 2004 Jan;10(1):80-6
14702637
J Clin Invest. 1989 Jul;84(1):145-54
2544622
Cell. 2006 Dec 15;127(6):1109-22
17112576
Circulation. 1989 Aug;80(2):390-400
2526698
Endocrinology. 2008 Feb;149(2):483-91
17991722
J Biol Chem. 2003 Dec 5;278(49):48617-26
12970365
FASEB J. 2000 Jul;14(10):1345-51
10877827
N Engl J Med. 1990 Sep 13;323(11):757-8
2143809
J Nephrol. 1998 Nov-Dec;11(6):296-9
10048495
Annu Rev Nutr. 1987;7:187-208
3300732
N Engl J Med. 2000 Jul 27;343(4):246-53
10911006
J Biol Chem. 2007 Jan 19;282(3):2038-46
17082193
Am J Physiol Endocrinol Metab. 2006 May;290(5):E864-9
16291573
Am J Physiol. 1985 Nov;249(5 Pt 2):F753-8
4061660
Nat Med. 2001 Aug;7(8):941-6
11479627
Proc Natl Acad Sci U S A. 2003 Mar 18;100(6):3404-9
12621153
Diabetes. 2009 Mar;58(3):710-7
19074984
Endocr Rev. 2006 Feb;27(1):47-72
16291870
Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15924-9
14676330
J Clin Invest. 2006 Mar;116(3):590-7
16511591
Circulation. 2001 Jul 17;104(3):342-5
11457755
PLoS Biol. 2004 Oct;2(10):e294
15328533
FASEB J. 2003 Dec;17(15):2299-301
14525942
Circulation. 2004 Feb 10;109(5):594-600
14769680