Seminars in medicine of the Beth Israel Deaconess Medical Center. Neuroendocrine responses to starvation and weight loss.
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Adipose Tissue↗
Biomedical subjects
R J Seeley
Publications and source records attributed to R J Seeley.
Glucagon-like peptide-1 and satiety.
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Animals↗
The new biology of body weight regulation.
A growing body of evidence suggests that energy balance (the difference between energy intake and expenditure) and body fuel stores in the form of adipose tissue are maintained by the body within a narrow range. This regulation of adiposity is mediated by the secretion of hormonal signals into the circulation in proportion to body adipose stores and their subsequent actions on brain systems that control caloric intake and energy expenditure. As a result, changes in energy balance sufficient to alter fuel stores elicit compensatory changes in energy intake and expenditure that return fat stores to their regulated level. Recent scientific break-through have identified the key components of this physiologic system. These include the circulating signals, leptin (the hormone encoded by the ob gene that is secreted by fat cells) and the pancreatic hormone insulin; and brain peptides such as neuropeptide Y, which is released from nerve terminals in the hypothalamus to elicit changes in feeding behavior and energy expenditure that mediate adaptive changes in energy balance. This article reviews the discovery of leptin and its receptor and discusses the interaction of leptin and insulin with the hypothalamic neuropeptide Y system. These observations provide a basis for understanding how weight lost during a period of negative energy balance (because of the inability to consume and/or store sufficient energy to meet ongoing energy demands) is eventually recovered. As our understanding of this weight-regulatory system increases, new insights into the causes of human obesity are likely to follow. Such insights may yield improvements in the medical and nutrition management of obese patients.
Animals↗
Adrenalectomy increases sensitivity to central insulin.
When infused into the third ventricle of rats, insulin dose-dependently reduces food intake and body weight, with doses of 1 mU/day and lower being ineffective. Because corticosterone functionally antagonizes many of insulin's peripheral actions, and because corticosterone acts in the brain to enable hyperphagia under some conditions, a subthreshold dose of insulin (1 mU/day), or its saline vehicle, was infused into the third ventricle of adrenalectomized (ADX) and sham-ADX male Long-Evans rats. Sham-ADX rats that received insulin or saline had no significant change of food intake or body weight over a 2-week interval. Likewise, saline-infused ADX were unaffected. In contrast, ADX rats receiving insulin had a significant reduction of food intake and body weight. These results suggest that the absence of circulating glucocorticoids increases the brain's sensitivity to insulin, and that insulin in the brain acts to lower food intake and body weight via a glucocorticoid-sensitive mechanism.
Adrenalectomy↗
The effect of intragastric ethanol on meal size in the rat.
Although ethanol is a calorically dense substance, little is known about the mechanisms by which those calories are detected, nor how they effect subsequent intake of other calories. In the current study, four doses of ethanol (0, 1, 2, and 3.5 g/kg) were administered to rats prior to 30-min access to a sucrose solution. The effect of ethanol (EtOH) to impact sucrose intake was compared to that of another carbohydrate, glucose, matched for calories, and to NaCl solutions matched to the osmotic properties of the glucose. A final set of conditions provided calories in the form of EtOH as well as osmoles in the form of NaCl to match the combined caloric and osmotic properties of the glucose solutions. Aqueous solutions of EtOH and of glucose suppressed food intake in a dose-dependent fashion with glucose tending to be more effective than EtOH. NaCl in water did not suppress intake. Surprisingly, when NaCl was added to the EtOH solution the effect of EtOH to suppress food intake was completely ameliorated. Subsequent analysis of plasma EtOH levels showed that adding NaCl also reduced the rate at which EtOH appeared in the plasma. The results suggest that changes of short-term food intake caused by EtOH calories are produced by different inhibitory signals than those produced by other carbohydrates. While other carbohydrates generate preabsorptive signals within the stomach, ethanol appears to have to leave the stomach to inhibit further food intake.
Animals↗
Wasting illness as a disorder of body weight regulation.
Recent major breakthroughs in our understanding of the negative feedback control of body weight have modified our understanding of disorders characterized by both too much and too little body fat. On the one hand, defective negative feedback signalling in the form of leptin contributes to certain forms of obesity, at least in rodent models. On the other, excessive leptin-like signalling, potentially resulting from the elaboration of inflammatory cytokines, may contribute to the pathogenesis of wasting illness. With the rapid pace of progress that has occurred in this field in recent years, it seems likely that breakthroughs in the treatment of these catastrophic illnesses may follow in the wake of new insights into the physiology and pathophysiology of body weight regulation.
Body Weight↗
Central infusion of GLP-1, but not leptin, produces conditioned taste aversions in rats.
Leptin (ob protein) and glucagon-like peptide-1-(7-36) amide (GLP-1) are peptides recently proposed to be involved in the regulation of food intake. Although the ability of exogenous leptin and GLP-1 to modulate consummatory behavior is consistent with the suggestion that these peptides are endogenous regulatory agents, central administration of these peptides may have aversive side effects, which could explain the anorexia. In the present experiment, exposure to a saccharine taste was immediately followed by central administration of leptin or GLP-1 to determine if these drugs could produce a conditioned taste aversion (CTA) in rats. At doses equated for producing comparable reductions in short-term food intake, GLP-1, but not leptin, generated a robust CTA. Although leptin caused no aversion, this peptide was the only drug to cause relatively long-term reductions in food consumption (16 h) and body weight (24 h). Hence, the results indicate that central GLP-1 produces aversive side effects, and it is argued that these nonspecific effects may explain the anorectic actions of GLP-1.
Animals↗
Leptin increases hypothalamic pro-opiomelanocortin mRNA expression in the rostral arcuate nucleus.
Melanocortins are peptides, cleaved from the pro-opiomelanocortin (POMC) precursor, that act in the brain to reduce food intake and are potential mediators of leptin action. In the forebrain, melanocortins are derived from POMC-containing neurons of the hypothalamic arcuate nucleus. To test the hypothesis that these POMC neurons are regulated by leptin, we used in situ hybridization to determine whether reduced leptin signaling (as occurs in fasting), genetic leptin deficiency (in obese ob/ob mice), or genetic leptin resistance (in obese db/db mice) lower expression of POMC mRNA. We further hypothesized that leptin administration would raise hypothalamic POMC mRNA levels in leptin-deficient animals, but not in mice with defective leptin receptors. In wild-type mice (n = 12), fasting for 48 h lowered POMC mRNA levels in the rostral arcuate nucleus by 53%, relative to values in fed controls (n = 8; P < 0.001). Similarly, arcuate nucleus POMC mRNA levels were reduced by 46 and 70% in genetically obese ob/ob (n = 6) and db/db mice (n = 6), respectively, as compared with wild-type mice (n = 5) (P < 0.01 for both comparisons). Five daily intraperitoneal injections of recombinant murine leptin (150 microg) raised levels of POMC mRNA in the rostral arcuate nucleus of ob/ob mice (n = 8) by 73% over saline-treated ob/ob control values (n = 8; P < 0.01), but was without effect in db/db mice (n = 6). In normal rats, two injections of a low dose of leptin (3.5 microg) into the third cerebral ventricle (n = 15) during a 40-h period of fasting also increased POMC mRNA levels in the rostral arcuate nucleus to values 39% greater than those in vehicle-treated controls (n = 14; P = 0.02). We conclude that reduced central nervous system leptin signaling owing to fasting or to genetic defects in leptin or its receptor lower POMC mRNA levels in the rostral arcuate nucleus. The finding that leptin reverses this effect in ob/ob, but not db/db, mice suggests that leptin stimulates arcuate nucleus POMC gene expression via a pathway involving leptin receptors. These findings support the hypothesis that leptin signaling in the brain involves activation of the hypothalamic melanocortin system.
Animals↗
Central leptin stimulates corticosterone secretion at the onset of the dark phase.
Leptin, a hormone secreted by adipose tissue in proportion to body adiposity, is proposed to be involved in the central nervous regulation of food intake and body weight. In addition, evidence is emerging that leptin regulates neuroendocrine and metabolic functions as well, presumably via its action in the central nervous system (CNS). To investigate this regulatory effect of leptin, we infused 3.5 microg of human leptin directly into the third cerebral ventricle (i3vt) of lean male Long-Evans rats, 90 min before the onset of their dark phase. Before and after infusion, blood samples were withdrawn through indwelling catheters for assessment of hormonal (plasma corticosterone, insulin, leptin), autonomic (plasma norepinephrine, epinephrine), and metabolic (plasma glucose) parameters. I3vt leptin caused an increase in plasma corticosterone and plasma leptin levels relative to the control condition. The effects of i3vt leptin on corticosterone secretion became particularly apparent after the onset of the dark phase. The results of the present study indicate that i3vt leptin stimulates the hypothalamo-pituitary-adrenal (HPA) axis, particularly when rats normally encounter their largest meals. These results are consistent with the possibility that high circulating leptin levels may underlie the increased activity of the HPA axis that is generally characteristic of human obesity and most animal models of obesity.
Analysis of Variance↗
Identification of targets of leptin action in rat hypothalamus.
The hypothesis that leptin (OB protein) acts in the hypothalamus to reduce food intake and body weight is based primarily on evidence from leptin-deficient, ob/ob mice. To investigate whether leptin exerts similar effects in normal animals, we administered leptin intracerebroventricularly (icv) to Long-Evans rats. Leptin administration (3.5 microg icv) at the onset of nocturnal feeding reduced food intake by 50% at 1 h and by 42% at 4 h, as compared with vehicle-treated controls (both P < 0.05). To investigate the basis for this effect, we used in situ hybridization (ISH) to determine whether leptin alters expression of hypothalamic neuropeptides involved in energy homeostasis. Two injections of leptin (3.5 microg icv) during a 40 h fast significantly decreased levels of mRNA for neuropeptide Y (NPY, which stimulates food intake) in the arcuate nucleus (-24%) and increased levels of mRNA for corticotrophin releasing hormone (CRH, an inhibitor of food intake) in the paraventricular nucleus (by 38%) (both P < 0.05 vs. vehicle-treated controls). To investigate the anatomic basis for these effects, we measured leptin receptor gene expression in rat brain by ISH using a probe complementary to mRNA for all leptin receptor splice variants. Leptin receptor mRNA was densely concentrated in the arcuate nucleus, with lower levels present in the ventromedial and dorsomedial hypothalamic nuclei and other brain areas involved in energy balance. These findings suggest that leptin action in rat hypothalamus involves altered expression of key neuropeptide genes, and implicate leptin in the hypothalamic response to fasting.
Animals↗
Intraventricular neuropeptide Y does not stimulate food intake in the baboon.
In the present study, we examined the ability of the orexigenic peptide neuropeptide Y (NPY) to stimulate feeding when administered into the lateral ventricle of baboons. No increase of either meal size or total daily food intake was observed over the dose range tested (1-30 micrograms). These results suggest that, in the baboon, NPY may not be an orexigen as it is in other species.
Animals↗
The evaluation of insulin as a metabolic signal influencing behavior via the brain.
The intent of this paper is to evaluate decreases of food intake and body weight that occur when a peptide is administered to an animal. Using the pancreatic hormone insulin as an example, the case is made that endogenous insulin is normally secreted in response to circulating nutrients as well as in proportion to the degree of adiposity. Hence, its levels in the blood are a reliable indicator of adiposity. A further case is then made demonstrating that insulin is transported through the blood-brain barrier into the brain, where it gains access to neurons containing specific insulin receptors that are important in the control of feeding and metabolism. Finally, experimentally-induced changes of insulin in the brain cause predictable changes of food intake and body weight. Given these observations, the question is then asked: since endogenous insulin, acting within the brain, appears to decrease food intake, can a decrease of food intake caused by exogenous insulin administered into the same area of the brain be ascribed to the same, naturally-occurring response system, or should it be attributed to malaise or a non-specific depression of behavior? Arguments are presented supporting the former position that exogenous insulin, when administered in small quantities directly into the brain, taps into the natural caloric/metabolic system and hence influences food intake and body weight.
Animals↗
Endocrine regulation of food intake and body weight.
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Adipose Tissue↗
Learned tolerance to the corticosterone-increasing action of ethanol in rats.
Ethanol administration stimulates the hypothalamic-pituitary-adrenal (HPA) axis, resulting in increased plasma levels of corticosterone. As occurs with many other effects of ethanol, tolerance develops with repeated administration such that plasma corticosterone levels become less effected by subsequent ethanol administration. The present experiment explored the possibility that the environmental cues associated with the administration of ethanol can control the expression of tolerance to ethanol's corticosterone-elevating effects. Male Long-Evans rats received intragastric administrations of ethanol (3.2 g/ kg) in association with one set of environmental cues and intragastric saline in association with a different set of environmental cues. Plasma corticosterone levels were elevated after the first ethanol administration, but after the tenth ethanol administration, corticosterone levels failed to increase significantly above control values. After demonstrating tolerance, rats were administered ethanol in the saline-paired environment and plasma corticosterone levels were higher than in the ethanol-paired environment. This environmental specificity suggests that tolerance to the neuroendocrine effects of ethanol is not simply the result of long-term alterations in sensitivity of the HPA axis but is, at least in part, mediated by learned responses to cues that predict the effects of ethanol.
Animals↗
Intraventricular leptin reduces food intake and body weight of lean rats but not obese Zucker rats.
The protein encoded by the obese (ob) gene, leptin, is secreted from adipose tissue and is proposed to act in the brain as an important regulator of food intake and body weight. To investigate the direct effects of leptin within the CNS, we injected 3.5 microg of either mouse or human leptin into the third ventricle (ICV) of lean Long-Evans rats or obese (fa/fa) Zucker rats, in which obesity results from a mutation in the leptin receptor gene. ICV administration of leptin reduced 4-h food intake in both deprived and non-deprived lean rats. In addition, repeated ICV administration produced a long-lasting reduction in body weight while peripheral administration of the same dose had no effect. ICV administration of the same dose of leptin into the third ventricle of obese Zucker rats did not reduce food intake. These results are consistent with the hypothesis that leptin has direct actions in the CNS as an afferent signal related to the state of energy stores in adipose tissue. Furthermore, insensitivity to these central effects of leptin may be an important determinant of obesity.
Animals↗
A comparison of the effects of food deprivation and 2,5-anhydro-D-mannitol on metabolism and ingestion.
Using respiratory quotient as an index of metabolic state, we compared the effects of administrations of the fructose analogue 2,5-anhydro-D-mannitol (2,5-AM) at a dose of 300 mg/kg with the effect of 10 h of food deprivation. We measured behavioral and physiological responses of the animals receiving the two treatments, including food intake, energy expenditure, rates of carbohydrate and fatty acid utilization, and plasma levels of glucose, insulin, corticosterone, epinephrine, and norepinephrine. A vehicle-treated control group was also included. Fasting produced a greater food intake than 2,5-AM administration. Although plasma glucose, insulin, and norepinephrine levels were similar between the two treatments, plasma corticosterone and epinephrine levels were significantly elevated in animals receiving 2,5-AM. We conclude that although 2,5-AM can produce a metabolic state similar to fasting, as measured by an index of whole body metabolic state (respiratory quotient), there remain factors that influence food intake that are not similar in the two conditions.
Animals↗
Behavioral, endocrine, and hypothalamic responses to involuntary overfeeding.
The suppression of food intake after a period of forced overfeeding is potent and long lasting, yet little is known of the underlying mechanisms for this regulatory response. Rats were overfed via a surgically implanted gastrostomy tube. During overfeeding, plasma insulin and corticotropin-releasing hormone (CRH) mRNA in the paraventricular nucleus of the hypothalamus were elevated compared with controls and with overfed rats allowed 3 days to recover from the overfeeding regimen such that body weight returned to the level of controls. In contrast, rats that were not overfed but were pair-fed to the low spontaneous food intake of previously overfed rats lost weight and had significantly reduced plasma insulin and elevated mRNA for neuropeptide Y (NPY) in the arcuate nucleus of the hypothalamus. The results indicate that overfeeding produces an activation of hypothalamic CRH system that may contribute to the hypophagia that accompanies involuntary overfeeding. Furthermore, the hypothalamic NPY response to food restriction is not tied to low food intake per se, but rather to negative energy balance.
Animals↗
Central infusions of leptin and GLP-1-(7-36) amide differentially stimulate c-FLI in the rat brain.
Recently, glucagon-like peptide-1-(7-36) amide (GLP-1) and leptin have been implicated in the regulation of food intake. In the present study, we compared the effects of third ventricular administration (i3vt) of leptin (3.5 micrograms) and GLP-1 (10.0 micrograms) on short-term food intake and c-Fos-like immunoreactivity (c-FLI) in hypothalamic, limbic, and hindbrain areas in the rat. Relative to controls, infusion of leptin or GLP-1 (3 h before lights off) significantly reduced food intake over the first 2 h in the dark phase (53 and 63%, respectively). In different rats, infusion of leptin or GLP-1 elevated c-FLI in the paraventricular hypothalamus and central amygdala. Furthermore, leptin selectively elevated c-FLI in the dorsomedial hypothalamus, whereas GLP-1 selectively elevated c-FLI in the nucleus of the solitary tract, area postrema, lateral parabrachial nucleus, and arcuate hypothalamic nucleus. The fact that most of the c-FLI after leptin or GLP-1 administration was observed in separate regions within the central nervous system (CNS) suggests different roles for leptin and GLP-1 in the CNS regulation of food intake and body weight.
Animals↗