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

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

Large changes in human foetal pulmonary bombesin during development and acute respiratory distress syndrome

Modulation of hypothalamic and anterior pituitary galanin expression by estrogen in the rat

Pancreatic polypeptide meal response may predict gastric band induced weight loss

Neuropeptide Y (NPY) is a 36-amino-acid member of the pancreatic polypeptide family which was originally isolated by Tatemoto from porcine brain.' It shows a wide distribution throughout the mammalian nervous system, including the hypothalamus, and numerous endocrine systems and has been shown to affect the release of anterior pituitary hormones.* Central administration of NPY in rat blocks the release of growth hormone (GH),' thyrotropin (TSH),4*5 prolactin (PRL)4,5 and, under some circumstances, luteinizing hormone secretion (LH).3*s-6 NPY has also been reported to stimulate LH secretion in estrogen-primed female rats,6\" suggesting that this hormonal response to NPY depends critically on the animal's sex steroid background. When anterior pituitary cells from ovariectomised rats were tested in a perifusion system with various concentrations of NPY a significant dose-response stimulation of LH, GH and follicle stimulating hormone (FSH) release was observed.' Crowley noted a dose-dependent potentiation by NPY of LH stimulation by LH releasing hormone from anterior pituitary cell cultures obtained from ovariectomised rats.* Recent recognition that the anterior pituitary is a source of bioactive compounds, including many neuropeptides that may have a local functional role, prompted this study. The aim of this investigation was to determine whether NPY is present in the anterior pituitary, and if so to investigate its cellular localisation and regulation by endocrine factors. As a peptide may be present in a tissue either as a result of local synthesis or from transport of exogenously produced peptide, we have assayed tissues for both peptide and messenger RNA (mRNA) content. The precise cellular location of NPY was determined by immunocytochemistry .

M. A. Ghatei

Papers

Large changes in human foetal pulmonary bombesin during development and acute respiratory distress syndrome

Modulation of hypothalamic and anterior pituitary galanin expression by estrogen in the rat

Pancreatic polypeptide meal response may predict gastric band induced weight loss

Neuropeptide Y and the Anterior Pituitary

Expression of C-flanking peptide of human pro-bombesin in pulmonary and extra-pulmonary small cell carcinoma