The association of hypertension and obesity is poorly understood. Studies conducted in our laboratory over the last decade, in conjunction with recent clinical and epidemiological observations, suggest that hypertension in the obese is derived from a fundamental relationship between dietary intake and sympathetic nervous system (SNS) activity. The application of kinetic techniques to the measurement of norepinephrine (NE) turnover rate in sympathetically innervated tissues of laboratory rodents has defined a relationship between the SNS and dietary intake. Fasting or caloric restriction suppresses sympathetic activity in a variety of organs of the rat, including heart and interscapular brown adipose tissue. Overfeeding a mixed, palatable, "cafeteria" diet stimulates sympathetic activity in these same tissues. The stimulatory effect of mixed diets is due to the carbohydrate and fat content, because these two latter nutrients stimulate sympathetic activity even when total caloric intake is not increased. Insulinmediated glucose metabolism within central neurons associated with the ventromedial hypothalamus (VMH) plays an important role in the relationship between dietary intake and SNS activity as indicated by the following observations: (1) Hypoglycemia (noninsulin-mediated) is associated with suppression of the SNS (despite concomitant adrenal medullary stimulation); (2) 2-deoxyglucose, an intracellular inhibitor of glucose metabolism, decreases sympathetic activity. The effects of 2-deoxyglucose, furthermore, are not additive with those produced by caloric restriction; (3) Streptozotocin-induced diabetes is associated with suppressed sympathetic activity despite increased caloric consumption; (4) Insulin infusion in normal human subjects, with maintenance of the plasma glucose level, is associated with increased plasma NE levels and signs of cardiovascular stimulation; and (5) destruction of insulin-glucose sensitive neurons in the VMH of mice treated with gold thioglucose obliterates diet-induced changes in SNS obesity. Dietary alterations in sympathetic activity are related to the changes in metabolic rate that occur during underfeeding and overfeeding. From an evolutionary standpoint suppression of metabolism would prolong survival during famine. The capacity to dissipate calories taken in excess may have its origins in the mammalian response to proteindeficient diets, because increased consumption of a low protein diet could satisfy basic needs for nitrogen while avoiding excessive fuel storage. Low protein diets, furthermore, stimulate the SNS whereas protein, in distinction to carbohydrate and fat, does not increase sympathetic activity. The capacity to augment sympathetically mediated thermogenesis during overfeeding, therefore, provides a potential buffer against excessive energy storage. The relationship between dietary intake and sympathetic activity, and the role of insulin as mediator in this relationship, suggests an hypothesis to explain the association of hypertension and obesity. In the obese, hypertension has been linked to hyperinsulinemia in both clinical and epidemiological studies. Insulin-mediated sympathetic stimulation in the obese may be a compensatory mechanism to limit weight gain by increasing thermogenesis. The concomitant effects of hyperinsulinemia on the kidney and the sympathetic nervous system would, however, increase blood pressure by enhancing renal sodium reabsorption and stimulating the cardiovascular system. Hypertension in the obese, according to this formulation, may be viewed as the unfortunate by-product of mechanisms recruited to limit weight gain and maintain energy balance. Am J Hypertens 1989;2:125S-132S.