The role of prokineticin 2 in energy homeostasis

Abstract

Obesity is a growing public health problem as its prevalence continues to increase. The hypothalamus is a region of the brain important in regulating energy homeostasis via complex, interacting neuronal circuits and neuropeptides. The prokineticins are cysteine-rich secreted proteins involved in regulating a diverse range of physiological functions. Prokineticin 2 (PK2), a recently discovered 81 amino acid peptide, is highly expressed in the suprachiasmatic nucleus and prokineticin receptors are expressed in several hypothalamic regions involved in energy homeostasis. However, the role of PK2 in the regulation of food intake and body weight has not been investigated. The studies described in this thesis investigate the role of PK2 in energy homeostasis. Intracerebroventricular (ICV) administration of PK2 potently reduced food intake in rats. This effect was specific; ICV PK2 did not affect locomotor activity or behaviour nor did it alter energy expenditure. Immunoblockade of PK2 by ICV administration of anti-PK2 IgG resulted in an increase in food intake in satiated rats. Furthermore, fasting reduced hypothalamic PK2 mRNA expression by approximately 50% in 12- and 24- hour fasted rats. These results suggest that hypothalamic PK2 may have a physiological role in appetite regulation. ICV administration of PK2 in rats resulted in c-fos expression, suggesting neuronal activation, in the supraoptic nucleus, arcuate nucleus (ARC), paraventricular nucleus and anterior hypothalamic area. Direct injection of PK2 into these hypothalamic sites potently reduced food intake, suggesting that the anorexigenic effects of PK2 may be mediated via these hypothalamic areas. Hypothalamic explants treated with PK2 significantly increased a-melanocyte stimulating hormone (a-MSH) release. ICV coadministration of PK2 and agouti-related protein (AgRP) (a melanocortin receptor antagonist) attenuated the anorexigenic effect of PK2, suggesting that the ARC melanocortin system may mediate part of the anorexigenic effects of PK2. In accord with this, following central PK2 administration the majority (64%) of c-fos-expressing neurones in the ARC were pro-opiomelanocortin (ROMC)-expressing neurones. Chronic peripheral administration of PK2 in lean and obese mice significantly reduced food intake with no evidence of tachyphylaxis, resulting in a significant reduction in body weight in both types of mice. These studies have provided novel information about the effects and role of PK2 in energy homeostasis. I propose that endogenous PK2 may have a physiological role in appetite regulation and may be a new target for the development of anti obesity agents