Abstract-This study was conducted to evaluate the mechanisms in weight gain-induced blood pressure (BP) elevation focusing, in particular, on the contributions of sympathetic nervous system activity, fasting plasma insulin, and leptin to BP levels. The study design was longitudinal with a cohort of 1897 men. BP, pulse rate, body mass index (BMI), fasting plasma norepinephrine (NE), insulin, and leptin were measured at 6 and 12 months in those 172 lean normotensive, 79 obese normotensive, 64 lean untreated hypertensive, and 38 obese untreated hypertensive men whose BMI increased Ͼ10% during the first 6 months. At entry, levels of BP, pulse rate, plasma NE, insulin, and leptin in obese subjects, regardless of BP status, were significantly greater than those in lean subjects. The levels of plasma NE, insulin, and leptin increased with weight gain in the 4 study groups. In the subjects with BP elevation, the increase in pulse rate and plasma NE was significantly greater than that in the subjects without BP elevation at both 6 and 12 months for each of the 4 study groups, although the increase in BMI was similar between the subjects with and without BP elevation. In obese but not lean subjects, whether normotensive or hypertensive, the increases in plasma insulin and plasma leptin with weight gain were greater in the subjects with accompanying BP elevation compared with the subjects without BP elevation. On the other hand, at 6 months in lean subjects, the increase in plasma insulin with weight gain in the subjects with BP elevation was actually lower than that in the subjects without BP elevation. These results suggest that weight gain-induced sympathetic overactivity is more tightly linked to weight gain-induced BP elevation than the changes in plasma insulin and leptin that also accompany weight gain. It is probable that sympathetic nervous activation with weight gain is a major mechanism of blood pressure elevation. Hyperinsulinemia and hyperleptinemia may be ancillary factors that contribute to sympathetic nervous stimulation with weight gain. Key Words: obesity Ⅲ body mass index Ⅲ hypertension, obesity Ⅲ investigative techniques Ⅲ sympathetic nervous system Ⅲ leptin Ⅲ insulin O besity and obesity related-hypertension are major and growing, international health problems, described by the World Health Organization (WHO) in its "Global Burden of Disease" report. 1 Furthermore, it is well known that obesity is a leading risk factor for chronic arterial hypertension and coronary heart disease. 2 The plasma concentration of the adipocyte hormone, leptin, is elevated in human obesity, which is thought to represent a state of leptin "resistance." 3 Leptin has been shown to influence sympathetic nerve activity. 4,5 Collins et al reported that leptin increased norepinephrine (NE) turnover in intercapsular brown adipose tissue. 3 Shek et al 6 reported that in the animal models, chronic leptin infusion caused an increase in heart rate and blood pressure, suggesting a possible role for leptin in the development of obesity-r...