New information regarding neuronal circuits that control food intake and their hormonal regulation has extended our understanding of energy homeostasis, the process whereby energy intake is matched to energy expenditure over time. The profound obesity that results in rodents (and in the rare human case as well) from mutation of key signalling molecules involved in this regulatory system highlights its importance to human health. Although each new signalling pathway discovered in the hypothalamus is a potential target for drug development in the treatment of obesity, the growing number of such signalling molecules indicates that food intake is controlled by a highly complex process. To better understand how energy homeostasis can be achieved, we describe a model that delineates the roles of individual hormonal and neuropeptide signalling pathways in the control of food intake and the means by which obesity can arise from inherited or acquired defects in their function.

/pdf/central-nervous-system-control-of-food-intake-3fzq7jxirh.pdf

Central nervous system control of food intake

The assimilation, storage and use of energy from nutrients constitute a homeostatic system that is essential for life In vertebrates, the ability to store sufficient quantities of energy-dense triglyceride in adipose tissue allows survival during the frequent periods of food deprivation encountered during evolution However, the presence of excess adipose tissue can be maladaptive A complex physiological system has evolved to regulate fuel stores and energy balance at an optimum level Leptin, a hormone secreted by adipose tissue, and its receptor are integral components of this system Leptin also signals nutritional status to several other physiological systems and modulates their function Here we review the role of leptin in the control of body weight and its relevance to the pathogenesis of obesity

Leptin and the regulation of body weight in mammals

https://www.cell.com/cell/pdf/S0092-8674(00)80949-6.pdf

Orexins and Orexin Receptors: A Family of Hypothalamic Neuropeptides and G Protein-Coupled Receptors that Regulate Feeding Behavior

We describe a hypothalamus-specific mRNA that encodes preprohypocretin, the putative precursor of a pair of peptides that share substantial amino acid identities with the gut hormone secretin. The hypocretin (Hcrt) protein products are restricted to neuronal cell bodies of the dorsal and lateral hypothalamic areas. The fibers of these neurons are widespread throughout the posterior hypothalamus and project to multiple targets in other areas, including brainstem and thalamus. Hcrt immunoreactivity is associated with large granular vesicles at synapses. One of the Hcrt peptides was excitatory when applied to cultured, synaptically coupled hypothalamic neurons, but not hippocampal neurons. These observations suggest that the hypocretins function within the CNS as neurotransmitters.

/pdf/the-hypocretins-hypothalamus-specific-peptides-with-4pipr77drn.pdf

The hypocretins: Hypothalamus-specific peptides with neuroexcitatory activity

The novel neuropeptides called hypocretins (orexins) have recently been identified as being localized exclusively in cell bodies in a subregion of the tuberal part of the hypothalamus. The structure of the hypocretins, their accumulation in vesicles of axon terminals, and their excitatory effect on cultured hypothalamic neurons suggest that the hypocretins function in intercellular communication. To characterize these peptides further and to help understand what physiological functions they may serve, we undertook an immunohistochemical study to examine the distribution of preprohypocretin-immunoreactive neurons and fibers in the rat brain. Preprohypocretin-positive neurons were found in the perifornical nucleus and in the dorsal and lateral hypothalamic areas. These cells were distinct from those that express melanin-concentrating hormone. Although they represent a restricted group of cells, their projections were widely distributed in the brain. We observed labeled fibers throughout the hypothalamus. The densest extrahypothalamic projection was found in the locus coeruleus. Fibers were also seen in the septal nuclei, the bed nucleus of the stria terminalis, the paraventricular and reuniens nuclei of the thalamus, the zona incerta, the subthalamic nucleus, the central gray, the substantia nigra, the raphe nuclei, the parabrachial area, the medullary reticular formation, and the nucleus of the solitary tract. Less prominent projections were found in cortical regions, central and anterior amygdaloid nuclei, and the olfactory bulb. These results suggest that hypocretins are likely to have a role in physiological functions in addition to food intake such as regulation of blood pressure, the neuroendocrine system, body temperature, and the sleep–waking cycle.

https://www.jneurosci.org/content/jneuro/18/23/9996.full.pdf

Neurons Containing Hypocretin (Orexin) Project to Multiple Neuronal Systems

The hypothalamus plays a central role in the integrated regulation of energy homeostasis and body weight, and a number of hypothalamic neuropeptides, such as neuropeptide Y (ref. 1), galanin, CRH (ref. 3) and GLP-1 (ref. 4), have been implicated in the mediation of these effects. To discover new hypothalmic peptides involved in the regulation of body weight, we used differential display polymerase chain reaction to identify messenger RNAs that are differentially expressed in the hypothalamus of ob/+ compared with ob/ob C57B1/6J mice. We show here that one mRNA that is overexpressed in the hypothalamus of ob/ob mice encodes the neuropeptide melanin-concentrating hormone (MCH). Fasting further increased expression of MCH mRNA in both normal and obese animals. Neurons containing MCH are located in the zona incerta and in the lateral hypothalamus. These areas are involved in regulation of ingestive behaviour, but the role of MCH in mammalian physiology is unknown. To determine whether MCH is involved in the regulation of feeding, we injected MCH into the lateral ventricles of rats and found that their food consumption increased. These findings suggest that MCH participates in the hypothalamic regulation of body weight.

A role for melanin-concentrating hormone in the central regulation of feeding behaviour

The effects of wheel running on oral intake of amphetamine were examined in six male Sprague-Dawley rats given a 0.075-mg/ml amphetamine sulfate solution as their sole source of liquid, six rats given a 0.15-mg/ml amphetamine solution, and four rats given water as their sole source of liquid. All animals were housed in Wahmann running wheels and adjoining cages, and had ad lib access to ground Purina Chow. For the first 7 days of the experiment, the doors to the running wheels were closed; the wheels were then opened for 6 days. This cycle was repeated a second time. Animals drinking the 0.15-mg/ml amphetamine solution consumed significantly less food and gained less weight than animals in the other two groups. Although there was no difference in food intake between rats drinking water and rats drinking the 0.075-mg/ml amphetamine solution, rats in the water group gained significantly more weight than rats in the 0.075-mg/ml amphetamine group. With respect to drug intake, rats consumed significantly less amphetamine when running in the wheels than when access to the wheels was prohibited. Access to running wheels did not alter water intake. These latter results suggest that drug intake can be reduced by the provision of an alternate behavior.

Exercise attenuates oral intake of amphetamine in rats

Preferences for foods with varying levels of salt and fat differ as a function of dietary restraint and exercise but not menstrual cycle

Research has demonstrated that intake of palatable carbohydrates and fats enhanced morphine-induced analgesia (MIA) in Sprague–Dawley rats. To determine if the effects of palatable foods on nociceptive responses would generalize to other strains of animals and other opioid agonists, the present experiments investigated whether intake of palatable foods would: a) alter MIA in Long–Evans rats, and b) alter analgesia produced by drugs acting at kappa opioid receptors. In experiment 1, adult male Long–Evans rats were fed Purina chow alone or chow and either a 32% sucrose solution, a 0.15% saccharin solution, or hydrogenated vegetable fat. Using a tail-flick apparatus, nociceptive responses, measured as percent maximal possible effect (%MPE), were examined after morphine administration [0.0, 1.0, 3.0, and 6.0 mg/kg subcutaneously (SC)]. %MPEs varied directly as a function of dose and were significantly greater for rats fed chow and either sucrose or fat than for rats fed chow alone or chow and saccharin. Experiment 2 compared the analgesic effect of the kappa opioid receptor agonist U50,488H (0, 5.0, 10.0, and 20.0 mg/kg SC) in rats fed chow alone or chow and a 32% sucrose solution. Administration of U50,488H led to analgesia. However, %MPEs did not vary directly as a function of dose. %MPEs of rats fed chow and sucrose were significantly greater than those of rats fed chow alone after injections of 10.0 and 20.0 mg/kg U50,488H. Experiment 3 compared the analgesic effect of U50,488H (5.0, 10.0, 15.0, and 20.0 mg/kg SC) in rats fed chow alone or chow and either a 0.15% saccharin solution or hydrogenated vegetable fat. Administration of U50,488H led to analgesia. However, %MPEs did not vary directly as a function of dose or as a function of diet. %MPEs of rats fed chow and fat were significantly greater than those of rats fed chow alone after injection of 5.0 mg/kg U50,488H.

Jeanne Przypek

Papers

A role for melanin-concentrating hormone in the central regulation of feeding behaviour

A role for melanin-concentrating hormone in the central regulation of feeding behaviour

Exercise attenuates oral intake of amphetamine in rats

Preferences for foods with varying levels of salt and fat differ as a function of dietary restraint and exercise but not menstrual cycle

Dietary modulation of mu and kappa opioid receptor-mediated analgesia.