Mechanisms Underlying the Link Between the Hypothalamo-Pituitary-Adrenal Axis, Energy Balance and Susceptibility to Obesity
thesis
posted on 2017-03-26, 23:14 authored by Demunu Sakda Dharmadasa Hewa GalamulageWithin any
population, the cortisol response to adrenocorticotropin (ACTH) is highly
variable. We identified subpopulations of ewes that have high (HR) or low (LR)
cortisol responses to Synacthen (synthetic ACTH). The HR ewes exhibit a
metabolic, endocrine and behavioural phenotype that associates with increased
predisposition to obesity.
To delineate factors that underpin the differing cortisol responses to ACTH, the hypothalamo-pituitary adrenal (HPA) axis was characterized. Gene expression for corticotropin releasing hormone (CRH) and arginine vasopressin (AVP) in the PVN and POMC in the anterior pituitary was higher in HR than LR. Also in the PVN, oxytocin expression was lower in HR with no differences in glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) expression in LR and HR. In the adrenal gland, expression of the melanocortin 2 receptor and a range of steroidogenic enzymes were similar in HR and LR. Furthermore, adrenal weight, cortex: medulla ratio and adrenal cortisol content were similar in LR and HR. In response to CRH treatment, plasma cortisol levels were higher in HR, despite reduced secretion of ACTH. This suggests that divergent cortisol production in LR and HR manifest at the level of the adrenal gland, yet the mechanism remains to be elucidated.
In addition, this work sought to characterise mechanisms that underpin altered energy balance in LR and HR. The hypothalamic ‘appetite-regulating peptides’ exert reciprocal effects on food intake and energy expenditure. At steady state and at similar body weights and adiposity, proopiomelanocortin (POMC), neuropeptide Y (NPY) and agouti-related peptide (AgRP) mRNA levels were similar in the arcuate nucleus (ARC) whereas the expression of melanin concentrating hormone (MCH) and orexin were lower in the lateral hypothalamic area (LHA) of HR than LR. Gene expression for melanocortin receptors 3&4 (MC3R & MC4R) in the paraventricular nucleus (PVN) was lower in HR, which coincides with impaired satiety in response to intracerebroventricular infusion of αMSH. Thus increased predisposition to obesity in HR, may at least in part, be mediated by innate reduction in melanocortin signalling.
To further characterise the melanocortin pathway, the interplay between the HPA axis and melanocortin system was examined. Although MC3R and MC4R expression was lower in the PVN of HR compared to LR, expression of both receptors was similar in other hypothalamic nuclei. In the PVN, the percentage number of CRH or AVP cells receiving melanocortin fibre input was similar between the 2 groups. HR received a higher melanocortin input to oxytocin cells, possibly as a compensatory mechanism to maintain energy homeostasis.
Finally, two independent breeding studies were performed, to determine if cortisol responsiveness was heritable. The maternal cortisol response to ACTH correlated with that of the female offspring only, suggesting that this is a maternally inherited, sex-specific phenotype. Furthermore, postprandial thermogenesis in skeletal muscle was lower in lambs of HR ewes, which was consistent with the maternal phenotype.
In conclusion, identifying subpopulations of HR and LR individuals allows selection of animals with altered predisposition to obesity. This thesis begins to unravel the physiological mechanisms that lead to an ‘obese’ phenotype in HR.
To delineate factors that underpin the differing cortisol responses to ACTH, the hypothalamo-pituitary adrenal (HPA) axis was characterized. Gene expression for corticotropin releasing hormone (CRH) and arginine vasopressin (AVP) in the PVN and POMC in the anterior pituitary was higher in HR than LR. Also in the PVN, oxytocin expression was lower in HR with no differences in glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) expression in LR and HR. In the adrenal gland, expression of the melanocortin 2 receptor and a range of steroidogenic enzymes were similar in HR and LR. Furthermore, adrenal weight, cortex: medulla ratio and adrenal cortisol content were similar in LR and HR. In response to CRH treatment, plasma cortisol levels were higher in HR, despite reduced secretion of ACTH. This suggests that divergent cortisol production in LR and HR manifest at the level of the adrenal gland, yet the mechanism remains to be elucidated.
In addition, this work sought to characterise mechanisms that underpin altered energy balance in LR and HR. The hypothalamic ‘appetite-regulating peptides’ exert reciprocal effects on food intake and energy expenditure. At steady state and at similar body weights and adiposity, proopiomelanocortin (POMC), neuropeptide Y (NPY) and agouti-related peptide (AgRP) mRNA levels were similar in the arcuate nucleus (ARC) whereas the expression of melanin concentrating hormone (MCH) and orexin were lower in the lateral hypothalamic area (LHA) of HR than LR. Gene expression for melanocortin receptors 3&4 (MC3R & MC4R) in the paraventricular nucleus (PVN) was lower in HR, which coincides with impaired satiety in response to intracerebroventricular infusion of αMSH. Thus increased predisposition to obesity in HR, may at least in part, be mediated by innate reduction in melanocortin signalling.
To further characterise the melanocortin pathway, the interplay between the HPA axis and melanocortin system was examined. Although MC3R and MC4R expression was lower in the PVN of HR compared to LR, expression of both receptors was similar in other hypothalamic nuclei. In the PVN, the percentage number of CRH or AVP cells receiving melanocortin fibre input was similar between the 2 groups. HR received a higher melanocortin input to oxytocin cells, possibly as a compensatory mechanism to maintain energy homeostasis.
Finally, two independent breeding studies were performed, to determine if cortisol responsiveness was heritable. The maternal cortisol response to ACTH correlated with that of the female offspring only, suggesting that this is a maternally inherited, sex-specific phenotype. Furthermore, postprandial thermogenesis in skeletal muscle was lower in lambs of HR ewes, which was consistent with the maternal phenotype.
In conclusion, identifying subpopulations of HR and LR individuals allows selection of animals with altered predisposition to obesity. This thesis begins to unravel the physiological mechanisms that lead to an ‘obese’ phenotype in HR.
