The role of augurin in the hypothalamo-pituitary-adrenal axis and the regulation of food intake

Novel secreted peptides represent an important field of research because delineation of their function affords new insights into the pathophysiological processes causing disease, and provides opportunities for the development of pharmacological therapies. Augurin is a recently identified secreted peptide of unknown function expressed in the central nervous system (CNS), pituitary, and several endocrine tissues. Because of its expression pattern I hypothesised that augurin may be involved in the neuroendocrine system. I therefore investigated the effects of central injection of augurin on the hypothalamo-pituitary axes and food intake in male Wistar rats. Intracerebroventricular (ICV) or intraparaventricular nucleus (iPVN) injection of augurin increased plasma adrenocorticotrophic hormone (ACTH) and corticosterone levels compared with vehicle-injected controls. Augurin also increased the release of corticotrophin releasing hormone (CRH) from hypothalamic explants, and pre-treatment with a CRH receptor antagonist in vivo prevented the rise in ACTH and corticosterone caused by ICV augurin, suggesting activation the hypothalamo-pituitary-adrenal (HPA) axis via by the release of CRH from neurons in the PVN. In addition to stimulating the HPA axis, iPVN injection of augurin at the start of either the light or dark phase caused a robust increase in food intake. To assess whether augurin might have a physiological role in the regulation of the HPA axis or food intake, I investigated its endogenous distribution in the rat CNS using immunohistochemistry and in situ hybridisation histochemistry. Augurin positive neurons were present in several regions of the CNS including the hypothalamus and the dorsal vagal complex of the brainstem, a distribution consistent with a possible role in neuroendocrine function. Augurin is therefore anatomically positioned to play a role in the hypothalamic regulation of the HPA axis and food intake. While the data presented suggest a novel role for augurin, these are preliminary studies. Currently, little is known about the physiology of the augurin system. Further characterisation of the neuroanatomy, identification of receptors, and the development of receptor agonists and antagonists would provide further data on the physiological role of augurin, and on the potential therapeutic benefits of manipulating the augurin system

The role of augurin in the hypothalamo-pituitary-adrenal axis and the regulation of food intake

Novel secreted peptides represent an important field of research because delineation of their function affords new insights into the pathophysiological processes causing disease, and provides opportunities for the development of pharmacological therapies. Augurin is a recently identified secreted peptide of unknown function expressed in the central nervous system (CNS), pituitary, and several endocrine tissues. Because of its expression pattern I hypothesised that augurin may be involved in the neuroendocrine system. I therefore investigated the effects of central injection of augurin on the hypothalamo-pituitary axes and food intake in male Wistar rats. Intracerebroventricular (ICV) or intraparaventricular nucleus (iPVN) injection of augurin increased plasma adrenocorticotrophic hormone (ACTH) and corticosterone levels compared with vehicle-injected controls. Augurin also increased the release of corticotrophin releasing hormone (CRH) from hypothalamic explants, and pre-treatment with a CRH receptor antagonist in vivo prevented the rise in ACTH and corticosterone caused by ICV augurin, suggesting activation the hypothalamo-pituitary-adrenal (HPA) axis via by the release of CRH from neurons in the PVN. In addition to stimulating the HPA axis, iPVN injection of augurin at the start of either the light or dark phase caused a robust increase in food intake. To assess whether augurin might have a physiological role in the regulation of the HPA axis or food intake, I investigated its endogenous distribution in the rat CNS using immunohistochemistry and in situ hybridisation histochemistry. Augurin positive neurons were present in several regions of the CNS including the hypothalamus and the dorsal vagal complex of the brainstem, a distribution consistent with a possible role in neuroendocrine function. Augurin is therefore anatomically positioned to play a role in the hypothalamic regulation of the HPA axis and food intake. While the data presented suggest a novel role for augurin, these are preliminary studies. Currently, little is known about the physiology of the augurin system. Further characterisation of the neuroanatomy, identification of receptors, and the development of receptor agonists and antagonists would provide further data on the physiological role of augurin, and on the potential therapeutic benefits of manipulating the augurin system.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

GDF15 mediates the effects of metformin on body weight and energy balance.

Metformin, the world's most prescribed anti-diabetic drug, is also effective in preventing type 2 diabetes in people at high risk1,2. More than 60% of this effect is attributable to the ability of metformin to lower body weight in a sustained manner3. The molecular mechanisms by which metformin lowers body weight are unknown. Here we show-in two independent randomized controlled clinical trials-that metformin increases circulating levels of the peptide hormone growth/differentiation factor 15 (GDF15), which has been shown to reduce food intake and lower body weight through a brain-stem-restricted receptor. In wild-type mice, oral metformin increased circulating GDF15, with GDF15 expression increasing predominantly in the distal intestine and the kidney. Metformin prevented weight gain in response to a high-fat diet in wild-type mice but not in mice lacking GDF15 or its receptor GDNF family receptor α-like (GFRAL). In obese mice on a high-fat diet, the effects of metformin to reduce body weight were reversed by a GFRAL-antagonist antibody. Metformin had effects on both energy intake and energy expenditure that were dependent on GDF15, but retained its ability to lower circulating glucose levels in the absence of GDF15 activity. In summary, metformin elevates circulating levels of GDF15, which is necessary to obtain its beneficial effects on energy balance and body weight, major contributors to its action as a chemopreventive agent

Nutritional regulation of oligodendrocyte differentiation regulates perineuronal net remodeling in the median eminence.

The mediobasal hypothalamus (arcuate nucleus, ARH and median eminence, ME) is a key nutrient sensing site for the production of the complex homeostatic feedback responses required for the maintenance of energy balance. Here we show that refeeding after an overnight fast rapidly triggers proliferation and differentiation of oligodendrocyte progenitors, leading to the production of new oligodendrocytes in the ME specifically. During this nutritional paradigm, ME perineuronal nets (PNN), emerging regulators of ARH metabolic functions, are rapidly remodelled, and this process requires myelin regulatory factor (Myrf) in oligodendrocyte progenitors. In genetically obese ob/ob mice, nutritional regulations of ME oligodendrocyte differentiation and PNN remodelling are blunted, and enzymatic digestion of local PNN increases food intake and weight gain. We conclude that MBH PNN are required for the maintenance of energy balance in lean mice and are remodelled in the adult ME via the nutritional control of oligodendrocyte differentiation

GDF15 mediates the effects of metformin on body weight and energy balance.

Metformin, the world’s most prescribed anti-diabetic drug, is also effective in preventing Type 2 diabetes in people at high risk1,2. Over 60% of this effect is attributable to metformin’s ability to lower body weight in a sustained manner3. The molecular mechanisms through which metformin lowers body weight are unknown. In two, independent randomised controlled clinical trials, circulating levels of GDF15, recently described to reduce food intake and lower body weight through a brain stem-restricted receptor, were increased by metformin. In wild-type mice, oral metformin increased circulating GDF15 with GDF15 expression increasing predominantly in the distal intestine and the kidney. Metformin prevented weight gain in response to high fat diet in wild-type mice but not in mice lacking GDF15 or its receptor GFRAL. In obese, high fat-fed mice, the effects of metformin to reduce body weight were reversed by a GFRAL antagonist antibody. Metformin had effects on both energy intake and energy expenditure that required GDF15. Metformin retained its ability to lower circulating glucose levels in the absence of GDF15 action. In summary, metformin elevates circulating levels of GDF15, which are necessary for its beneficial effects on energy balance and body weight, major contributors to its action as a chemopreventive agent