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In order to determine whether insulin binding to receptors in the central nervous system can be modified by changes in energy balance, hypothalami from 48 h food deprived and 14 day food restricted (8 or 4 g chow/day) rats were removed and insulin binding to partially purified membranes from both medial and lateral hypothalamic regions was studied. Hypothalamic insulin concentration was measured in similarly treated animals. Although hypothalamic insulin concentration did not vary, insulin binding to lateral receptors was significantly lower than that obtained from the medial region. After prolonged food restriction, binding to medial receptors was significantly reduced in comparison to controls, whereas binding in the lateral region remained unchanged; differences were most pronounced at near-physiological insulin concentrations. Changes in per cent specific [125I]insulin binding were associated with corresponding changes in maximal insulin-binding capacity, the latter being inversely related to receptor affinity for this hormone. These results are consistent with the hypothesis that insulin, acting via hypothalamic receptors, may serve as a metabolic feedback signal linking the periphery with central body weight regulatory mechanisms.

Acid extracts of bovine hypothalamus stimulate lipogenic activity in adipose tissue. We employed a rat fat cell bioassay system to determine whether tissue concentrations of the active material vary as a function of spontaneous alterations in energy balance in hibernators and/or the obesity resulting from bilateral electrolytic lesions of the ventromedial area of the hypothalamus in rats. When hypothalamic extracts and partially purified plasma were fractionated using reverse-phase high-pressure liquid chromatography, both the void volume and material eluting 17 min after the start of a 25-min linear methanol gradient enhanced glucose incorporation into total lipid. Activities eluting with these two fractions were positively correlated with one another and were independent of insulin. The results indicate that a hypothalamic lipogenic factor (LHF) is detectable in plasma, that hypothalamic and circulating LHF concentrations vary in a reciprocal manner, and that elevations in plasma LHF concentration are associated with insulin resistance. The data suggest that the central regulation of lipogenesis is at least partially mediated by a hypothalamic humoral factor reaching fat depots via the circulation.

We have previously shown that [125I]insulin binding to medial hypothalamic receptors is attenuated following 14 days of food restriction. Such rats are characterized by considerably reduced circulating insulin levels with unchanged hypothalamic insulin concentration. The present data demonstrate that, in contrast to the effects of starvation, [125I]insulin binding to hypothalamic receptors from rats made hyperinsulinaemic by daily injections of protamine zinc insulin (4-6 U/rat/day for 14 days) is unaffected by this manipulation, even though hypothalamic insulin concentration in insulin-injected animals was significantly higher than in saline-injected controls. Insulin binding to partially purified membranes from the medial hypothalamic region was significantly greater than that from the lateral area, confirming a finding in our earlier study. Insulin treatment was associated with slight reductions in maximal insulin-binding capacity of medial hypothalamic receptors, a tendency which appeared to be compensated by reciprocal changes in receptor affinity for this hormone. The data indicate that hypothalamic insulin receptors are not regulated by peripheral or even central insulin levels per se; it appears, rather, that some other, as yet unidentified, correlate(s) of significantly altered food intake and/or body weight can modify hypothalamic insulin receptor function. Perhaps such modifications could, in turn, participate in the activation of regulatory mechanisms involved in correcting energy imbalance.

Insulin binding to receptors in a partially purified hypothalamic membrane preparation is altered by prolonged starvation. To define further the relationship between hypothalamic insulin binding and energy balance, we studied the Richardson's ground squirrel, a hibernator that exhibits spontaneous 6- to 8-mo body weight cycles when kept in constant conditions. Isolated pancreatic islets from squirrels killed during the weight gain phase had greater glucose-stimulated insulin secretion than those from weight loss phase animals, and adipocytes showed significantly greater glucose incorporation into total lipid in response to insulin. Differences in lipogenesis were not attributable to changes in insulin-binding capacity. Hypothalamic tissue from weight gain phase animals bound more insulin than that from weight loss phase animals. Maximal binding was correlated with pancreatic islet responsiveness and maximal insulin-stimulated lipogenesis. The strong positive correlation between peripheral metabolic events associated with spontaneous alterations in energy balance and the binding kinetics of hypothalamic insulin receptors suggests that insulin may play an important role in the central regulation of body weight.

[125I]insulin binding to partially purified hypothalamic membranes is reduced during prolonged starvation, and changes in hypothalamic insulin binding capacity correlate well with spontaneous variations in energy balance in ground squirrels. To determine whether an insulin binding impairment in the central nervous system can be observed during the early expression of genetic obesity, both obese (fa/fa) and phenotypically lean (Fal-) Zucker rats were studied at 6 weeks of age. Hypothalamic tissue from fa/fa rats bound significantly less hormone than that from the lean animals, but binding was not changed in tissue from cerebral cortex. It is concluded that a defect in insulin binding to hypothalamic receptors in Zucker fatty rats may contribute to the development of weight gain in these animals.