Induction of brain-region-specific forms of obesity by agouti.
Disruption of melanocortin (MC) signaling, such as by ectopic Agouti overexpression, leads to an obesity syndrome with hyperphagia, obesity, and accelerated body weight gain during high-fat diet. To investigate where in the brain disruption of MC signaling results in obesity, long-term Agouti expression was induced after local injections of recombinant adeno-associated viral particles in selected brain nuclei of adult rats. Agouti expression in the paraventricular nucleus, a hypothalamic region with a high density of MC receptors, induced acute onset hyperphagia and rapid weight gain that persisted for at least 6 weeks. In contrast, obesity and hyperphagia developed with a 3 week delay when Agouti was expressed in the dorsal medial hypothalamus. Agouti expression in the lateral hypothalamus (LH) did not affect food intake and body weight during regular diet, despite the presence of MC receptors in this region. However, during exposure to a high-fat diet, animals with Agouti expression in the LH exhibited a marked increase in body weight. Here we show that the LH is important for the protection against diet-induced obesity by controlling caloric intake during consumption of a high-fat diet. Together, this study provides evidence that different aspects of the Agouti-induced obesity syndrome, such as hyperphagia and diet responsiveness, are mediated by distinct brain regions and opens challenging opportunities for further understanding of pathophysiological processes in the development of the obesity syndrome.
Kas
Martien J H
MJ
Rudolf Magnus Institute of Neuroscience, Department of Pharmacology and Anatomy, University Medical Centre Utrecht, 3584 CG Utrecht, The Netherlands.
Tiesjema
Birgitte
B
van Dijk
Gertjan
G
Garner
Keith M
KM
Barsh
Gregory S
GS
ter Brake
Olivier
O
Verhaagen
Joost
J
Adan
Roger A H
RA
D054366:Agouti Signaling Protein; D054369:Agouti-Related Protein; D000818:Animals; D002460:Cell Line; D004041:Dietary Fats / Q000633:toxicity; D002149:Energy Intake; D006801:Humans; D006963:Hyperphagia / Q000235:genetics / Q000503:physiopathology*; D007031:Hypothalamus / Q000503:physiopathology*; D007033:Hypothalamus, Middle / Q000503:physiopathology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D008297:Male; D009478:Neuropeptide Y / Q000096:biosynthesis / Q000235:genetics; D009765:Obesity / Q000235:genetics / Q000503:physiopathology* / Q000517:prevention & control; D009928:Organ Specificity; D010286:Paraventricular Hypothalamic Nucleus / Q000503:physiopathology; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D044101:Receptors, Melanocortin / Q000096:biosynthesis / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015430:Weight Gain / Q000187:drug effects / Q000235:genetics
D054366:Agouti Signaling Protein; D054369:Agouti-Related Protein; D004041:Dietary Fats; D036341:Intercellular Signaling Peptides and Proteins; D009478:Neuropeptide Y; D011506:Proteins; D012333:RNA, Messenger; D044101:Receptors, Melanocortin; D011993:Recombinant Fusion Proteins