Obesity is a major public health problem worldwide and increased body weight enhances the risk for hypertension, diabetes and coronary artery disease. Leptin, a peptide hormone produced by adipocytes in proportion to the degree of adiposity, plays an important role in the regulation of appetite, energy expenditure and body weight as well as sympathetic nervous system (SNS) activity and blood pressure (BP). Despite leptin levels being elevated in obesity, leptin’s ability to suppress appetite is markedly attenuated, whereas its effect to increase SNS and BP are maintained, suggesting that obesity is associated with “selective” leptin resistance. The mechanisms for this differential regulation of appetite, SNS activity, and BP, however, are still unclear. We have recently found that changes in ambient temperature result in differential control of appetite. SNS activity and BP by leptin.We performed preliminary studies in lean wild-type (WT) mice to investigate the chronic metabolic and cardiovascular responses to leptin at thermoneutral zone (30oC,TNZ) and cold temperature (15oC), and we observed “selective” leptin resistance when ambient temperature was reduced from TNZ to 15oC. For instance, chronic leptin infusion for 7 days at 15oC markedly raised BP and heart rate (HR) while the reduction in food intake was only modest and transient. Conversely, at TNZ leptin infusion caused pronounced and sustained suppression of food intake but failed to raise BP and HR. Thus, investigation of leptin’s chronic actions at different ambient temperatures reveals divergent control of appetite and BP regulation by leptin and may provide important insights into the fundamental mechanisms by which leptin controls cardiovascular and metabolic functions independently.
Activation of leptin receptors (LR) in different areas of the brain could provide a partial explanation for differential control of appetite, energy expenditure, HR and BP regulation by leptin. In addition, each of three main intracellular signaling pathways activated by the LR (STAT3, IRS2 and SHP2) may contribute differently to the multiple actions of leptin. However, little is known about the specific areas of the brain, including the forebrain and brainstem, as well as the role of STAT3, IRS2 and SHP2 signaling in mediating the chronic effects of leptin on appetite, energy expenditure, HR and BP regulation at TNZ and during cold ambient temperature. We propose that activation of LRs in the forebrain, particularly in the hypothalamus, play a major role in controlling appetite at TZN but has only minor impact on energy expenditure, HR and BP regulation. Conversely, LRs in the brainstem are proposed to mediate important effects of leptin on energy expenditure, HR and BP, especially during cold exposure, but have minimal impact on appetite regulation. We also hypothesize that STAT3 is involved mainly in appetite regulation by leptin, while IRS2 and SHP2 are more important for the regulation of BP and energy expenditure.To test these hypotheses, we will employ state-of-the-art methods to measure BP, HR, food intake and whole-body oxygen consumption (VO2) 24 hr/day at TNZ and cold exposure in chronically instrumented mice in which selective deletion of LRs, STAT3, IRS2 and SHP2 proteins in specific nuclei in the forebrain and brainstem is achieved by using Cre-Lox technology.
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