Abstract-Obesity is strongly associated with hypertension and cardiovascular disease. Several central and peripheral abnormalities that can explain the development or maintenance of high arterial pressure in obesity have been identified. These include activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system. Obesity is also associated with endothelial dysfunction and renal functional abnormalities that may play a role in the development of hypertension. The continuing discovery of mechanisms regulating appetite and metabolism is likely to lead to new therapies for obesity-induced hypertension. Better understanding of leptin signaling in the hypothalamus and the mechanisms of leptin resistance should facilitate therapeutic approaches to reverse the phenomenon of selective leptin resistance. Other hunger and satiety signals such as ghrelin and peptide YY are potentially attractive therapeutic strategies for treatment of obesity and its complications. These recent discoveries should lead to novel strategies for treatment of obesity and hypertension. (Hypertension. 2005;45:9-14.)Key Words: hypertension, obesity Ⅲ nervous system, sympathetic renal Ⅲ vasculature Ⅲ kidney T he increasing prevalence of obesity worldwide is a serious health hazard. This is particularly true for the United States, where Ϸ300 000 deaths each year are associated with being overweight and obese. Obese individuals are at increased risk for diabetes, hypertension, renal failure, and other cardiovascular diseases. Clinical and animal studies have confirmed a strong relationship between obesity and hypertension. 1 Accumulating evidence points to visceral obesity as the most important risk factor for hypertension and cardiovascular disease. 2 Recent work has identified several mechanisms that have therapeutic implications as potential causes of obesity-hypertension. In addition, to these advances, there has also been a revolution in our understanding of neuroendocrine mechanisms regulating appetite, metabolism, and adiposity since the discovery of leptin just Ͼ10 years ago. If, as we predict, these advances soon translate into safe and effective pharmacological treatment of obesity, this would also greatly impact the management of obesityhypertension. Consequently, we briefly review some highlights on advances in understanding the pathophysiology of obesity in addition to highlights on obesity-induced hypertension. New Developments in Neurobiology of ObesityThe identification of leptin represents the most significant breakthrough in obesity research because it helped unravel the architecture of neuroendocrine circuitry that controls appetite and energy homeostasis. Leptin is an adipocyte-derived hormone that acts in the hypothalamus to regulate appetite and energy expenditure. Recently, increasing attention has been dedicated to leptin transduction mechanisms (Figure 1). The leptin receptor is a single transmembrane protein belonging to the cytokine-receptor superfamily known to signal via the janus kinase/signal ...

This study prompts three conclusions: (1) leptin-deficient ob/ob mice and agouti yellow obese mice have contrasting blood pressure responses to obesity, (2) obesity does not invariably increase arterial pressure in mice, and (3) the arterial pressure response to obesity may depend critically on the underlying genetic and neuroendocrine mechanisms.

Leptin, a hormone secreted by adipose tissue, acts to inhibit appetite and promote metabolism, thereby reducing body weight. Leptin also increases sympathetic activity and arterial pressure. Several murine models of obesity, including agouti obese mice, exhibit resistance to the anorexic and weight-reducing effects of leptin. Hypertension in agouti mice has been attributed to hyperleptinemia. These observations pose a seeming paradox. If these mice are leptin-resistant, then how can leptin contribute to hypertension? We tested the novel hypothesis that these mice have selective leptin resistance, with preservation of the sympathoexcitatory action despite resistance to the weight-reducing actions. Leptin-induced decreases in food intake and body weight were less in agouti obese mice than in lean littermates. In contrast, leptin-induced increases in sympathetic nerve activity did not differ in obese and lean mice. These findings support the concept of selective leptin resistance, with resistance to the metabolic actions of leptin but preservation of the sympathoexcitatory actions. This finding may have potential implications for human obesity, which is associated with elevated plasma leptin and is thought to be a leptinresistant state. If leptin resistance is selective in obese humans, then leptin could contribute to sympathetic overactivity and its adverse consequences in human obesity. Diabetes 51:439 -442, 2002 L eptin suppresses appetite and promotes weight loss (1,2). In addition, leptin increases sympathetic nerve activity (3) and arterial pressure (4,5). Agouti yellow obese (Ay) mice develop obesity because of blockade of hypothalamic melanocortin-4 receptors secondary to ectopic expression of agouti peptide (6 -9). The agouti mice are resistant to the satiety and weightreducing actions of leptin (2), even though they do not have mutations in the leptin receptor gene.Ay mice have higher arterial pressure than their lean littermates (10). The agouti mice have hyperleptinemia (2,5), and a recent study indicated that the elevated leptin contributes to regulation of arterial pressure (5).This brings us to a seeming paradox and to the focus of this study. How can leptin contribute to regulation of arterial pressure in agouti mice if these mice are resistant to the effects of leptin? In this study, we tested the hypothesis that Ay mice have selective leptin resistance, with preservation of the sympathetic actions of leptin despite resistance to the metabolic actions. RESEARCH DESIGN AND METHODSWe tested the effects of exogenous leptin on body weight, food intake, and sympathetic nerve activity in agouti yellow obese (C57BL/6J-A y ) and lean littermates (C57BL/6Ja/a) aged 12-14 weeks, which were purchased from Jackson Laboratories. All procedures were approved by the University of Iowa Animal Research Committee. Recording of renal sympathetic nerve activity. To measure direct multifiber renal sympathetic nerve activity (SNA) in anesthetized mice, we made a left retroperitoneal incision and carefully isolated a ner...