Student Theses and Dissertations


Makoto Ishii

Date of Award


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RU Laboratory

Deans Office


obesity, leptin, GPR7


Classic lesion experiments from the 1940s have established the hypothalamus as playing an essential role in controlling energy homeostasis. Gold-thioglucose (GTG) induces lesions in the ventromedial nucleus of the hypothalamus (VMH) resulting in hyperphagia and obesity. To identify genes involved in the hypothalamic regulation of energy homeostasis, we employed a screen to search for genes that were dysregulated in GTG induced obese mice. In this screen, GPR7, the endogenous G protein-coupled receptor (GPCR) for the recently identified ligands neuropeptide B (NPB) and neuropeptide W (NPW), was found to be specifically down-regulated after GTG treatment. The physiological role of GPR7 was investigated by generating and analyzing mice with targeted disruption of GPR7. Male GPR7-/- mice developed an adult-onset obesity syndrome that progressively worsened with age and was greatly exacerbated when animals were fed a high fat diet. Male GPR7A mice were hyperphagic and had decreased energy expenditure and locomotor activity. These mice also had an abnormal response to fasting-induced feeding but not to glucoprivic-induced feeding suggesting that central response to glucose was normal. The hypothalamic RNA levels of neuropeptide Y and proopiomelanocortin in male GPR7-/- mice were more indicative of a lean state than a leptin deficient "starved" state. Furthermore, ob/ob GPR7-/- and Ay/a GPR7-/- double mutant male mice were heavier than normal ob/ob or Ay/a male mice suggesting that the obesity of GPR7 -/- mice is independent of leptin and melanocortin signaling. Interestingly, female GPR7-/- mice did not show any significant weight increase or associated metabolic defects. Additionally, other behavioral paradigms were investigated in the GPR7-/- mice. Baseline sleep-wake cycles, circadian rhythms, anxiety-like behaviors, and depression-like behaviors were all normal in GPR7-/- mice. Therefore, these behavioral disorders can not account for the feeding disorders seen in GPR7-/- mice. In aggregate, these data strongly suggest a physiological role for GPR7 and its endogenous ligands, NPB and NPW, as a catabolic signaling pathway independent of leptin and melanocortin pathways. Future studies of GPR7, its ligands, and the GPR7 knockout mice will further elucidate the full range of physiological functions of this novel signaling pathway.


A thesis presented to the faculty of The Rockefeller University in partial fulfillment of the requirements for the degree of Doctor of Philosophy.

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