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

Abstract

. Sim1 gene dosage modulates the homeostatic feeding response to increased dietary fat in mice. Am J Physiol Endocrinol Metab 287: E105-E113, 2004. First published February 24, 2004 10.1152/ajpendo.00446.2003.-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 A MEMBER OF THE basic helix-loop-helix-PAS family of nuclear transcription factors is encoded by the Sim1 gene (6). Mouse Sim1 was originally cloned by virtue of its homology with Drosophila single-minded, a master regulator of central nervous system midline neurogenesis (9, 11). In mammals, Sim1 plays a more specialized role in brain development. The only anatomic defect that has been identified in homozygous sim1-knockout mice, which die shortly after birth, is the complete absence of neurons of the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus (22). The PVN produces corticotropin-releasing hormone, thyrotropin-releasing hormone, and somatostatin, which regulate ACTH, thyroid-stimulating hormone, and growth hormone secretion by the anterior pituitary. The PVN and SON also synthesize oxytocin and vasopressin, which are released by the posterior pituitary. In addition to its endocrine functions, the PVN has been known for decades to play a key role in energy balance. Lesions of the PVN in adult dogs (15) or rats (19) result in hyperphagic obesity. The PVN integrates orexigenic (e.g., neuropeptide Y and Agouti-related peptide) and anorexigenic (e.g., ␣-melanocyte-stimulating hormone and...

Adenoviral-Mediated Modulation ofSim1Expression in the Paraventricular Nucleus Affects Food Intake

“…The Sim1 gene copy number has a major influence on food intake in mice and in humans (Holder et al, 2000(Holder et al, , 2004Michaud et al, 2001). Our paradigm of stereotaxic injection of adenoviruses into the PVN does not easily permit correlations between physiological end points and levels of gene expression, because only a subset of the PVN is infected.…”

“…In the absence of Sim1, virtually all cells of the PVN are missing and mice die shortly after birth, presumably because of these defects. In contrast, mice with only one copy of a Sim1 mutant allele survive but show increased weight gain after 4 weeks of age (Michaud et al, 2001;Holder et al, 2004). Previous studies suggest that Sim1 haploinsufficiency induces obesity by increasing food intake, without decreasing energy expenditure (Michaud et al, 2001;Holder et al, 2004) (Duplan et al, unpublished observations).…”

Mouse models for the central melanocortin system

“…Interestingly, Sim1 is highly expressed in the PVN of the hypothalamus [42]. Sim1 heterozygous mice develop hyperphagic obesity, increased linear growth, hyperinsulinemia and elevated feeding efficiency [27]. MTII injection fails to reduce food intake in Sim1 heterozygous mice.…”

Studies of the SIM1 gene in relation to human obesity and obesity-related traits

“…2 Mice heterozygous for the null Sim1 allele have a hypocellular PVN, and are severely obese with increased food intake. 3,4 In addition, a balanced translocation disrupting the SIM1 gene is associated with severe, early-onset obesity, hyperphagia and increased linear growth in a patient. 5 Although the balanced translocation disrupting the SIM1 gene may be the cause of obesity and hyperphagia in that particular patient, the possibility that altered expression of other genes owing to the chromosome rearrangement might contribute to her phenotype cannot be excluded.…”