Disruption of leptin signaling contributes to cardiac hypertrophy independently of body weight in mice.
BACKGROUND
Whether left ventricular hypertrophy (LVH) in obesity results from increased hemodynamic load or altered neurohormonal signaling remains controversial. Dysregulation of leptin, a neurohormone essential to energy homeostasis, is implicated in the pathogenesis of obesity. Because leptin has cardiovascular bioactivity, we hypothesized that disruption of leptin signaling mediates the development of obesity-associated LVH.


RESULTS
We measured left ventricular (LV) wall thickness and LV mass with echocardiography in mice lacking leptin (ob/ob, n=15) or functional receptor (db/db, n=10) and controls at 2, 4, and 6 months of age. None of the mice had LVH at 2 months. Progressive obesity developed in ob/ob and db/db mice. At 6 months, LVH occurred in ob/ob and db/db compared with controls. We observed corresponding myocyte hypertrophy by light microscopy. To separate the direct contribution of leptin deficiency from mechanical effects of obesity, we induced weight loss in 6- to 8-month-old ob/ob mice either by leptin infusion or caloric restriction. Mice in both groups lost similar weight compared with placebo-treated controls. Leptin infusion completely reversed the increase in wall thickness with partial resolution of myocyte hypertrophy, whereas calorie-restricted mice had no decrease in wall thickness and a lesser change in myocyte size.


CONCLUSIONS
Together these data show that the effect of leptin on LV remodeling is not attributable to weight loss alone, indicating that leptin has antihypertrophic effects on the heart, either directly or through a leptin-regulated neurohumoral pathway. Disruption of leptin signaling may represent a novel mechanism in LVH and related cardiovascular disorders.
Barouch
Lili A
LA
Department of Medicine, Division of Cardiology, Johns Hopkins Hospital, 600 North Wolfe St, Baltimore, Md 21287, USA.
Berkowitz
Dan E
DE
Harrison
Robert W
RW
O'Donnell
Christopher P
CP
Hare
Joshua M
JM
D000818:Animals; D001835:Body Weight / Q000235:genetics; D006332:Cardiomegaly / Q000150:complications / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D006352:Heart Ventricles / Q000473:pathology; D006439:Hemodynamics; D006720:Homozygote; D020738:Leptin / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000473:pathology; D009765:Obesity / Q000150:complications / Q000235:genetics*; D009929:Organ Size / Q000235:genetics; D011956:Receptors, Cell Surface / Q000172:deficiency* / Q000235:genetics; D054411:Receptors, Leptin; D015398:Signal Transduction; D020257:Ventricular Remodeling / Q000235:genetics
D020738:Leptin; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; C515447:leptin receptor, mouse