Role of Selective Leptin Resistance in Diet-Induced Obesity Hypertension Kamal Rahmouni, 1,2 Donald A. Morgan, 1,2 Gina M. Morgan, 1,2 Allyn L. Mark, 1,2 and William G. Haynes 1,2 Leptin is an adipocyte-derived hormone that plays a key role in the regulation of body weight through its actions on appetite and metabolism. Leptin also increases sym- pathetic nerve activity (SNA) and blood pressure. We tested the hypothesis that diet-induced obesity is asso- ciated with resistance to the metabolic actions of leptin but preservation of its renal SNA and arterial pressure effects, leading to hypertension. Mice were fed a high- fat diet for 10 weeks to induce moderate obesity. The decrease in food intake and body weight induced by intraperitoneal or intracerebroventricular leptin was significantly attenuated in the obese mice. Regional SNA responses to leptin were differentially altered in diet-induced obese mice. Renal SNA response to leptin was preserved, whereas lumbar and brown adipose tis- sue SNA responses were attenuated in obese mice. Radiotelemetric arterial pressure was 10 mmHg higher in obese mice. Furthermore, the increase in arterial pressure in response to long-term (12 days) leptin treatment was preserved in obese mice. Thus, mice with diet-induced obesity exhibit circulating hy- perleptinemia and resistance to the metabolic actions of leptin. However, there is preservation of the renal sympathetic and arterial pressure responses to leptin, which represent a potential mechanism for the adverse cardiovascular consequences of obesity. Diabetes 54: 2012–2018, 2005 O besity is an important risk factor for cardiovas- cular morbidity and mortality. The mechanisms linking obesity and cardiovascular disorders remain poorly understood. Several mecha- nisms have been implicated, including overactivity of the sympathetic nervous system (1–3). Recent evidence indi- cates that leptin may play a role in the high arterial pressure associated with excess weight gain. Leptin, a 167–amino acid protein secreted by adipocytes (4), relays a satiety signal to the central nervous system where it acts to decrease appetite and increase energy expenditure through activation of the sympathetic nerve outflow to thermogenic tissues, such as the brown adipose tissue (BAT) (5). Leptin also causes a significant and dose- dependent sympathetic excitation to nonthermogenic tis- sues, such as the kidneys and adrenal glands (5,6). Renal sympathetic activation to leptin suggests that this hor- mone plays a role in cardiovascular regulation. Indeed, chronic infusion and transgenic overexpression of leptin has been shown to increase arterial blood pressure and heart rate (7,8). In contrast, leptin deficiency, as in the ob/ob mouse, leads to decreased arterial pressure, despite severe obesity (9). Plasma leptin levels are significantly elevated in obese individuals compared with lean subjects (10,11). There- fore, it has been suggested that most obese subjects have resistance to the anorectic and weight-reducing effects of leptin. Emerging evidence suggest that leptin resistance associated with obesity may be selective and spare some actions of leptin. For example, in agouti obese mice, there is resistance to the metabolic effects of leptin, but leptin still contributes to the hypertension observed in this model (8,9). Recently, we have demonstrated that agouti obese mice have selective leptin resistance with preserved renal sympathetic activation despite the loss of the ano- rectic and weight-reducing effects of leptin. The effects of leptin on food intake and body weight were significantly less in agouti obese mice than in lean controls, whereas the increase in renal sympathetic nerve outflow was preserved in agouti obese mice (12,13). However, the relevance of this mouse model to human obesity is un- clear, as no form of human obesity caused by overexpres- sion of agouti or agouti-related proteins has been reported. In the present study, we examined the role of leptin in hypertension associated with an acquired form of obesity, namely diet-induced obesity. Dietary models of obesity are widely accepted models for common human obesity. This is based on the observation that diet-induced obesity in animal models recapitulates the features of obesity in humans, including metabolic and cardiovascular changes (14). We tested the hypothesis that diet-induced obesity is associated with resistance to the metabolic actions of leptin but preservation of the cardiovascular sympathetic actions, leading to hypertension. RESEARCH DESIGN AND METHODS Male C57BL/6J mice, at the age of 5– 6 weeks, were obtained from The Jackson Laboratories (Bar Harbor, ME). Mice were weighed and randomly assigned to normal diet (Harlan Teklad, Madison, WI) or high-fat diet (D12451; Research Diets, New Brunswick, NJ). Normal diet was composed of protein (18.62%), fat (6.25%), fibers (4.53%), and nitrogen-free extracts (53%). High-fat diet From the 1 Hypertension Genetics Specialized Center of Research, Cardiovas- cular Center, University of Iowa, Iowa City, Iowa; and the 2 Department of Internal Medicine, University of Iowa, Iowa City, Iowa. Address correspondence and reprint requests to Kamal Rahmouni, PhD, Cardiovascular Research Center, 524 MRC, University of Iowa, Iowa City, IA 52242. E-mail: kamal-rahmouni@uiowa.edu. Received for publication 18 March 2005 and accepted in revised form 18 April 2005. BAT, brown adipose tissue; SNA, symapathetic nerve activity. © 2005 by the American Diabetes Association. 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. 2012 DIABETES, VOL. 54, JULY 2005