Simultaneous deletion of ghrelin and its receptor increases motor activity and energy expenditure.

Administration of chemically synthesized ghrelin (Ghr) peptide has been shown to increase food intake and body adiposity in most species. However, the biological role of endogenous Ghr in the molecular control of energy metabolism is far less understood. Mice deficient for either Ghr or its receptor (the growth hormone secretagogue receptor, GHS-R1a) seem to exhibit enhanced protection against high-fat diet-induced obesity but do not show a substantial metabolic phenotype on a standard diet.

Peptide YY regulates bone turnover in rodents.

Background & Aims: Peptide YY (PYY) and pancreatic polypeptide (PPY) are members of the neuropeptide Y peptide family. The neuropeptide Y receptor signaling pathway has been implicated in a number of physiologic processes, including the regulation of energy balance and bone mass. To investigate the contribution of endogenous PYY and PPY to these processes, we generated both Pyy- and Ppy-deficient mice.

Agouti-related protein-deficient mice display an age-related lean phenotype.

Endogenous modulators of the central melanocortin system, such as the agouti-related protein (AgRP), should hold a pivotal position in the regulation of energy intake and expenditure. Despite this, AgRP-deficient mice were recently reported to exhibit normal food intake, body weight gain, and energy expenditure. Here we demonstrate that 2- to 3-month-old Agrp null mice do in fact exhibit subtle changes in response to feeding challenges (fasting and MCR agonists) but, of more significance and magnitude, exhibit reduced body weight and adiposity after 6 months of age.

Absence of ghrelin protects against early-onset obesity.

The gut peptide ghrelin, the endogenous ligand for the growth hormone secretagogue receptor, has been implicated not only in the regulation of pituitary growth hormone (GH) secretion but in a number of endocrine and nonendocrine functions, including appetitive behavior and carbohydrate substrate utilization. Nevertheless, recent genetic studies have failed to show any significant defects in GH levels, food intake, or body weight in adult ghrelin-deficient (Ghrl-/-) mice. Here we demonstrate that male Ghrl-/- mice are protected from the rapid weight gain induced by early exposure to a high-fat diet 3 weeks after weaning (6 weeks of age).

Resistance to diet-induced obesity in mice globally overexpressing OGH/GPB5.

We identified a glycoprotein hormone beta-subunit (OGH, also called GPB5) that, as a heterodimer with the alpha-subunit GPA2, serves as a second ligand for the thyroid-stimulating hormone receptor. Mice in which the OGH gene is deleted (OGH-/-) are indistinguishable from WT littermates in body weight, response to high-fat diet, metabolic parameters, body composition, and insulin tolerance. Mice engineered to transgenically globally overexpress OGH (OGH-TG) develop approximately 2-fold elevations in their basal thyroid levels and weigh slightly less than WT littermates despite increased food intake because of an increase in their metabolic rates.

Absence of the lipid phosphatase SHIP2 confers resistance to dietary obesity.

Genetic ablation of Inppl1, which encodes SHIP2 (SH2-domain containing inositol 5-phosphatase 2), was previously reported to induce severe insulin sensitivity, leading to early postnatal death. In the previous study, the targeting construct left the first eighteen exons encoding Inppl1 intact, generating a Inppl1(EX19-28-/-) mouse, and apparently also deleted a second gene, Phox2a. We report a new SHIP2 knockout (Inppl1(-/-)) targeted to the translation-initiating ATG, which is null for Inppl1 mRNA and protein.

Genetic deletion of ghrelin does not decrease food intake but influences metabolic fuel preference.

Ghrelin is a recently identified growth hormone (GH) secretogogue whose administration not only induces GH release but also stimulates food intake, increases adiposity, and reduces fat utilization in mice. The effect on food intake appears to be independent of GH release and instead due to direct activation of orexigenic neurons in the arcuate nucleus of the hypothalamus. The effects of ghrelin administration on food intake have led to the suggestion that inhibitors of endogenous ghrelin could be useful in curbing appetite and combating obesity.

Hypothalamic control of energy balance: different peptides, different functions.

Energy balance is maintained via a homeostatic system involving both the brain and the periphery. A key component of this system is the hypothalamus. Over the past two decades, major advances have been made in identifying an increasing number of peptides within the hypothalamus that contribute to the process of energy homeostasis.

Cocaine- and amphetamine-regulated transcript in the arcuate nucleus stimulates lipid metabolism to control body fat accrual on a high-fat diet.

Previous studies have indicated a relationship between cocaine- and amphetamine-related transcript (CART) and leptin. The present study used quantitative PCR and in situ hybridization to examine this CART-leptin relationship in different animal models. With CART injection, the function of this pathway was also investigated.

Peptides that regulate food intake: orexin gene expression is increased during states of hypertriglyceridemia.

Previous reports implicate the orexins in eating and body weight regulation. This study investigated possible functional relationships between hypothalamic orexins and circulating hormones or metabolites. In situ hybridization and quantitative PCR were used to examine orexin expression in the perifornical hypothalamus (PF) of rats and mice on diets varying in fat content and with differential propensity toward obesity.