Sim1 gene dosage modulates the homeostatic feeding response to increased dietary fat in mice

• Published in: American journal of physiology: endocrinology and metabolism Vol. 287; no. 1; pp. E105 - E113
• Main Authors: Holder, J. Lloyd, Jr, Zhang, Ling, Kublaoui, Bassil M, DiLeone, Ralph J, Oz, Orhan K, Bair, Chi Horng, Lee, Ying-Hue, Zinn, Andrew R
• Format: Journal Article
• Language: English
• Published: United States 01.07.2004
• Subjects: Aging - physiology; Animals; Basic Helix-Loop-Helix Transcription Factors; Body Constitution - physiology; Body Weight - physiology; Dietary Fats - administration & dosage; Dietary Fats - metabolism; Feeding Behavior - physiology; Female; Gene Dosage; Gene Expression Regulation - physiology; Homeostasis - physiology; Hyperphagia - physiopathology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Repressor Proteins - genetics; Repressor Proteins - metabolism; Sex Factors
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00446.2003

1 McDermott Center for Human Growth and Development and Department of Internal Medicine, 2 Department of Psychiatry, and 3 Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390; and 4 Academia Sinica, Taipei, Taiwan Submitted 2 October 2003 ; accepted in final form 18 February 2004 Haploinsufficiency of the transcription factor gene Sim1 has been previously implicated in hyperphagic obesity in humans and mice. To investigate the relation between Sim1 dosage and hyperphagia, we generated sim1- knockout mice and studied their growth and feeding behavior. Heterozygous mice weaned on standard chow consumed 14% more food per day than controls and developed obesity, hyperinsulinemia, and hyperleptinemia. The sim1 heterozygous mice were also significantly longer than controls. Heterozygous animals had modestly increased feeding efficiency, suggesting reduced energy expenditure, but voluntary wheel-running activity did not differ significantly between the two groups. We studied the effect of dietary fat on the feeding behavior of heterozygous sim1 mutant mice. The tempo and severity of weight gain were much greater in animals weaned on a high-fat diet. When acutely challenged with increased dietary fat, sim1 heterozygous mice weaned on the chow diet markedly increased their food consumption and caloric intake, whereas control mice reduced the mass of food they consumed and maintained approximately isocaloric intake. In wild-type adult mice, we detected Sim1 expression in the paraventricular and supraoptic nuclei, as previously reported in neonates, as well as in the amygdala and lateral hypothalamus, all regions implicated in feeding behavior. Our results indicate that Sim1 gene dosage modulates the homeostatic feeding response to increased dietary fat and likely plays a physiological role in the regulation of energy balance. hypothalamus; transcription factor; feeding behavior Address for reprint requests and other correspondence: A. R. Zinn, Dept. of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8591 (E-mail: Andrew.Zinn{at}UTSouthwestern.edu ).