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.

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Central nervous system control of food intake

Cannon, Barbara, and Jan Nedergaard. Brown Adipose Tissue: Function and Physiological Significance. Physiol Rev 84: 277–359, 2004; 10.1152/physrev.00015.2003.—The function of brown adipose tissue i...

Brown Adipose Tissue: Function and Physiological Significance

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

Type 2 diabetes is characterized by impaired insulin secretion. Some but not all studies suggest that a decrease in beta-cell mass contributes to this. We examined pancreatic tissue from 124 autopsies: 91 obese cases (BMI >27 kg/m(2); 41 with type 2 diabetes, 15 with impaired fasting glucose [IFG], and 35 nondiabetic subjects) and 33 lean cases (BMI <25 kg/m(2); 16 type 2 diabetic and 17 nondiabetic subjects). We measured relative beta-cell volume, frequency of beta-cell apoptosis and replication, and new islet formation from exocrine ducts (neogenesis). Relative beta-cell volume was increased in obese versus lean nondiabetic cases (P = 0.05) through the mechanism of increased neogenesis (P < 0.05). Obese humans with IFG and type 2 diabetes had a 40% (P < 0.05) and 63% (P < 0.01) deficit and lean cases of type 2 diabetes had a 41% deficit (P < 0.05) in relative beta-cell volume compared with nondiabetic obese and lean cases, respectively. The frequency of beta-cell replication was very low in all cases and no different among groups. Neogenesis, while increased with obesity, was comparable in obese type 2 diabetic, IFG, or nondiabetic subjects and in lean type 2 diabetic or nondiabetic subjects. However, the frequency of beta-cell apoptosis was increased 10-fold in lean and 3-fold in obese cases of type 2 diabetes compared with their respective nondiabetic control group (P < 0.05). We conclude that beta-cell mass is decreased in type 2 diabetes and that the mechanism underlying this is increased beta-cell apoptosis. Since the major defect leading to a decrease in beta-cell mass in type 2 diabetes is increased apoptosis, while new islet formation and beta-cell replication are normal, therapeutic approaches designed to arrest apoptosis could be a significant new development in the management of type 2 diabetes, because this approach might actually reverse the disease to a degree rather than just palliate glycemia.

https://diabetes.diabetesjournals.org/content/diabetes/52/1/102.full.pdf

β-Cell Deficit and Increased β-Cell Apoptosis in Humans With Type 2 Diabetes

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

Under-nutrition is increasing in the ageing population; termed the anorexia of ageing, costing the NHS around £13 billion a year. Recent evidence suggests that this weight loss seen in ageing may be due to a reduction in appetite and energy intake. The mechanism of action is currently not known. It has recently been established that peptides released from the gastrointestinal tract have an influence on energy intake, for example PYY3-36 has been shown to potently reduce food intake . Some evidence suggests that there are alterations in gastrointestinal appetite hormones in ageing, but the data is limited and equivocal. The aim of this study was to investigate if the reduction in energy intake in older healthy volunteers is the result of a reduction in appetite, caused by an alteration in the release of gastrointestinal appetite hormones. Subjective feelings of appetite, energy intake at an ad libitum meal and alterations in gastrointestinal appetite hormone release were investigated in 58 healthy volunteers ranging from the ages of 20 to 92 years.

M. A. Ghatei

Papers

Anorexia of Ageing is Associated with Increased Post-Prandial Secretion of the Anorectic Gastrointestinal Hormone Peptide YY

Increased pressor effect of repeated doses of rat or porcine endothelin in the anaesthetised rat

Neuropeptide content of purified rat brain cholinergic synaptosome subpopulations.

Distribution and Molecular Characterization of Neuromedin U‐, Neuromedin B‐, and Bombesin‐like Immunoreactivity in the Amphibian Rana temporaria

Pancreastatin, a novel neuropeptide, is widely distributed throughout porcine brain, pituitary, spinal cord and dorsal root ganglia