Decreased binding to hypothalamic insulin receptors in young genetically obese rats.

[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.

Neurohumoral stimulation of lipogenesis during altered states of energy balance.

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.

Insulin and central regulation of spontaneous fattening and weight loss.

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.

Failure of chronic experimental hyperinsulinism to alter insulin binding to hypothalamic receptors in the rat.

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.

Starvation-induced changes in insulin binding to hypothalamic receptors in the rat.

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.

Spontaneous obesity and weight loss: insulin action in the dormouse.

Dormice (Glis glis) undergo spontaneous cyclic changes in food intake and body weight. These infradian cycles with a periodicity of about 2 mo are endogenously controlled, since they persist in conditions of constant temperature and photoperiod. To evaluate the role of insulin as an effector of hyperphagia and fattening in dormice, experiments were conducted to study pancreatic function and adipose tissue metabolism during several phases of the infradian cycle. During the weight loss phase, peripheral insulin resistance occurs in the absence of hyperinsulinism. This resistance is not corrected by weight loss. Weight loss phase animals showed poor glucose tolerance and an impaired in vitro glucose-stimulated insulin secretion; these were not attributable to reduced pancreatic insulin content. Although basal glucose transport and basal, as well as insulin-stimulated, glucose utilization in isolated adipocytes were depressed during the weight loss phase, insulin-stimulated transport was significant. The data offer no evidence that insulin has a direct causal role in the development of spontaneous obesity in this species.

Spontaneous obesity and weight loss: insulin binding and lipogenesis in the dormouse.

Obese dormice (Glis glis) become anorexic during the weight loss phase of the 2-mo (infradian) body weight cycle. We have shown previously that this phase is characterized by severe insulin resistance, manifested by impaired insulin-stimulated glucose utilization in isolated adipocytes. Contrary to other obesity models, the insulin resistance was not accompanied by hyperinsulinism. In the present study, impaired lipogenesis was associated with decreased maximal insulin-binding capacity (due to a reduction in receptor concentration) and a postreceptor defect, which were exacerbated rather than attenuated during weight loss.

Lipolytic activity in brown adipocytes during spontaneous weight cycles in dormice.

In vitro release of glycerol from isolated brown adipocytes into incubation medium was measured using axillary brown adipose tissue (BAT) removed from dormice during various phases of the infradian body weight cycle. Lipolytic activity in BAT was reduced during the weight loss phase in comparison to the weight gain phase. In the absence of deep and prolonged torpor, BAT does not appear to act as an effector of weight loss for hibernators undergoing large cyclical fluctuations in body energy content.

Pituitary beta-endorphin content during spontaneous food intake and body weight cycles in the dormouse, Glis glis.

Pituitary beta-endorphin content was measured in dormice during several distinct phases of the infradian body weight cycle. No significant differences in opiate content among groups were found. It appears unlikely that pituitary concentrations of beta-endorphin have etiological significance in the development of spontaneous obesity in hibernators.

Efficiency of food utilization during body weight gain in dormice (Glis glis).

During spontaneous body weight gain in dormice, Glis glis, progressive increases in the efficiency of food utilization as defined by weight gain (g)/food intake (g), and parallel increases in mean daily food intake were observed. Towards the end of the weight gain period, there was an abrupt drop in feeding efficiency with no significant change in food intake even when the latter was expressed relative to an index of each animal's "metabolic mass" (body weightkg0.62). Animals whose body weight increases followed a return to ad lib feeding after prolonged food restriction showed marked decreases in feeding efficiency from initially high values which were independent of changes in food intake. These results are discussed in relation to the sliding set point concept of body weight regulation in hibernators.

Persistence of body weight cycles in dormice maintained with a limited food supply.

Dormice kept under food restriction for several months continued to exhibit body weight cycles with characteristic periods of about 2 months, despite an impaired ability to attain the high body weight levels observed in ad libitum conditions. These results imply that the cycle is controlled by a mechanism whose properties are more consistent with asn endogenous oscillator than with a sequence of stages, in which the relevant stages are defined by upper and lower body weight limits.