Glucocorticoids and Melanocortins in the Regulation of Body Weight in Humans

Abstract

The last decade witnessed a dramatic increase in kowledge concerning regulation of body weight and obesity. According to recent concepts constancy of body weight is a side product of regulatory events which ensure constant glucose fluxes to the brain. Within these control systems glucocorticoids and melanocortins play a fundamental role at several sites. The melanocortin neurons in the arcuate nucleus are important mediators of the feedback effects of leptin and insulin. Glucocorticoid and mineralocorticoid receptors in hippocampal neurons are crucial as they define the balance between glucose allocation processes and food intake. Thereby, the hippocampal structures determine the setpoint for bodyweight regulation. Novel approaches to treatment of obesity must aim at manipulating these brain structures.

Key words

Bodyweight - Obesity - Arcuate nucleus - Hippocampus - Ventral medial hypothalamus - Lateral hypothalamus - Melanocortins - A-MSH - Glucocorticoids - Mineralocorticoids

References

• 1 Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman J M. Positional cloning of the mouse obese gene and its human homologue.  Nature. 1994;  372 425-432
• 2 Peters A, Schweiger U, Fruhwald-Schultes B, Born J, Fehm H L. The neuroendocrine control of glucose allocation.  Exp Clin Endocrinol Diabetes. 2002;  110 199-211
• 3 Chipkin S R, van Bueren A, Bercel E, Garrison C R, McCall A L. Effect of dexamethasone in vivo and in vitro on hexose transport in brain microvasculature.  Neurochemical Research. 1998;  23 645-652
• 4 Feldman S, Conforti N, Weidenfeld J. Limbic pathways and hypothalamic neurotransmitters mediating adrenocortical responses to neural stimuli.  Neurosci Biobehav Rev. 1995;  19 235-240
• 5 Molina P E, Abumrad N N. Contribution of excitatory amino acids to hypoglycemic counter- regulation.  Brain Res. 2001;  899 201-208
• 6 de Kloet E R, Vreugdenhil E, Oitzl M S, Joels M. Brain corticosteroid receptor balance in health and disease.  Endocr Rev. 1998;  19 269-301
• 7 Schwartz M W, Woods S C, Seeley R J, Barsh G S, Baskin D G, Leibel R L. Is the energy homeostasis system inherently biased toward weight gain?.  Diabetes. 2003;  52 232-238
• 8 Ibrahim N, Bosch M A, Smart J L, Qiu J, Rubinstein M, Ronnekleiv O K, Low M J, Kelly M J. Hypothalamic proopiomelanocortin neurones are glucose responsive and express K(ATP) channels.  Endocrinology. 2003;  144 1331-1340
• 9 Spanswick D, Smith M A, Mirshamsi S, Routh V H, Ashford M L. Insulin activates ATP-sensitive K+ channels in hypothalamic neurones of lean, but not obese rats.  Nat Neurosci. 2000;  3 757-758
• 10 Spanswick D, Smith M A, Groppi V E, Logan S D, Ashford M L. Leptin inhibits hypothalamic neurones by activation of ATP-sensitive potassium channels.  Nature. 1997;  390 521-525
• 11 Arvaniti K, Huang Q, Richard D. Effects of leptin and corticosterone on the expression of corticotropin-releasing hormone, agouti-related protein, and proopiomelanocortin in the brain of ob/ob mouse.  Neuroendocrinology. 2001;  73 227-236
• 12 Beaulieu S, Gagne B, Barden N. Glucocorticoid regulation of proopiomelanocortin messenger ribonucleic acid content of rat hypothalamus.  Mol Endocrinol. 1988;  2 727-731
• 13 Born J, Lange T, Kern W, McGregor G P, Bickel U, Fehm H L. Sniffing neuropeptides: a transnasal approach to the human brain.  Nat Neurosci. 2002;  5 514-516
• 14 Fehm H L, Smolnik R, Kern W, McGregor G P, Bickel U, Born J. The melanocortin melanocyte-stimulating hormone/adrenocorticotropin(4 - 10) decreases body fat in humans.  J Clin Endocrinol Metab. 2001;  86 1144-1148
• 15 O’Donohue T L, Handelmann G E, Miller R L, Jacobonitz D. N-Acetylation regulates the behavioral activity of α-melanotropin in a multineurotransmitter neuron.  Science. 1982;  215 1125-1127