Hormonal Responses that Regulate the Metabolic Benefits of Exercise: The Contribution of the Melanocortin System and the Fibroblast Growth Factor 21 (FGF21) Signaling Pathway
Year: 2014
Type: article
Abstract: Exercise has benefits on body and fat mass, glucose metabolism, and lipid metabolism.Likewise, exercise is an effective therapy against the metabolic syndrome.Yet, the molecular pathways underlying the advantageous effects of exercise are imperfectly understood.Emerging evidence suggests that the melanocortin system and the fibroblast growth factor 21 (FGF21) signaling axis, two endocrine pathways involved in regulation of energy homeostasis, are mediators of exercise benefits.The melanocortin system, and specifically the melanocortin 4 receptor (MC4R), is required for normal regulation of energy balance, and glucose and lipid homeostasis.Inactivation of MC4R results in severe obesity and metabolic syndrome in rodents and humans.The overlapping roles of MC4R activation and exercise in regulation of energy homeostasis indicate that melanocortin signaling might regulate the exercise response.Moreover, evidence from our group that illustrates hypothalamic melanocortin signaling following exercise has lead us to hypothesize that the melanocortin system mediates metabolic benefits of exercise.To test this, we provided wild-type (WT) and Mc4r -/-(HOM) rats with ad libitum running wheel iii exercise for 5 weeks.We found that, despite reduced capacity for exercise, voluntary running activity reduced body and fat mass gain, and improved glucose and lipid metabolism of HOM rats suggesting that the melanocortin system might be involved in the capacity for voluntary exercise but is not required to mediate exercise-induced metabolic benefits.Next, we examined the function of FGF21 in the exercise response.FGF21 is an endocrine factor regulated by nutritional status with numerous beneficial effects on metabolism.Exogenous FGF21 improves insulin sensitivity, glucose, and lipid homeostasis in diabetic animal models and is currently being investigated for use in humans to treat type 2 diabetes.In line with the therapeutic effects of FGF21, there is evidence that FGF21 regulates the exercise response.Yet, the metabolic function of FGF21 during exercise is largely undescribed.We hypothesized that FGF21 is required for exercise-mediated regulation of energy homeostasis.We tested this by challenging WT and FGF21-deficient (Fgf21 -/-) mice to high-fat diet and allowing access to voluntary running wheel exercise for 12 weeks.WT and Fgf21 -/-mice exhibited similar running behavior.Exercise was effective in reducing development of diet-induced obesity by reducing body/fat mass gain, and in improving plasma lipidemia independent of genotype.However, despite the effect on energy balance, exercise failed to improve glucose tolerance in FGF21deficient mice.Furthermore, Fgf21 -/-mice had impaired adaptation to chronic exercise including reduced AMPK activity in skeletal muscle.These results demonstrate that FGF21 activity is required for the beneficial effects of exercise on glucose metabolism.Overall, we conclude that exercise is effective in ameliorating metabolic syndrome caused by MC4R inactivation and in preventing the development of dietary obesity.Yet, exercise may require supplementation with other therapeutics in prevention of diet-induced metabolic syndrome in the context of impaired FGF21 signaling.To the members of the Obici Laboratory, especially Jack Magrisso, Michael Haas, Joram Mul, and Sonia Lipp-you have been an incredible source of knowledge and help throughout the trials and tribulations of our projects.I will miss our conversations and seeing you every day.I hope to stay in touch despite the distance that will be between us.Also, a special thanks to Joram for providing the Mc4r -/-rat line and for your constant encouragement and guidance throughout my studies.I would also like to acknowledge my mom, Randy, Sissy, Susan, and my nieces and nephew-you have always supported and encouraged me in my endeavors, and you have been a source of unconditional love throughout my life.I love you
Author: Christine Loyd
Institution: University of Cincinnati
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2619787175