Sim1 Haploinsufficiency Impairs Melanocortin-Mediated Anorexia and Activation of Paraventricular Nucleus Neurons

Abstract

Single-minded 1 (SIM1) is one of only six genes implicated in human monogenic obesity. Haploinsufficiency of this hypothalamic transcription factor is associated with hyperphagic obesity and increased linear growth in both humans and mice. Additionally, Sim1 heterozygous mice show enhanced hyperphagia and obesity in response to a high-fat diet. Thus the phenotype of Sim1 haploinsufficiency is similar to that of agouti yellow (Ay), and melanocortin 4 receptor (Mc4r) knockout mice, both of which are defective in hypothalamic melanocortin signaling. Sim1 and Mc4r are both expressed in the paraventricular nucleus (PVN). Here we report that Sim1 heterozygous mice, which have normal energy expenditure, are hyperphagic despite having elevated hypothalamic proopiomelanocortin (Pomc) expression. In response to the melanocortin agonist melanotan-2 (MTII) they exhibit a blunted suppression of feeding yet increase their energy expenditure normally. They also fail to activate PVN neurons in response to the drug at a dose that induces robust c-Fos expression in a subset of Sim1 PVN neurons in wild-type mice. The resistance to melanocortin signaling in Sim1 heterozygotes is not due to a reduced number of Sim1 neurons in the PVN. Hypothalamic Sim1 gene expression is induced by leptin and MTII treatment. Our results demonstrate that Sim1 heterozygotes are resistant to hypothalamic melanocortin signaling and suggest that Sim1-expressing PVN neurons regulate feeding, but not energy expenditure, in response to melanocortin signaling.

Mouse models for the central melanocortin system

“…MTII injection fails to reduce food intake in Sim1 heterozygous mice. But like in wild-type mice, metabolic rate in Sim1 heterozygous mice is increased in response to MTII treatment [35]. BAC transgenic mice over-expressing Sim1 are resistant to diet-induced obesity.…”

Rare variants in single-minded 1 (SIM1) are associated with severe obesity

“…The obesity phenotype of Sim1 +/-mice closely resembles that of mice lacking the melanocortin 4 receptor (Mc4r) with increased linear growth and increased feeding efficiency in addition to an increase in food intake (3,4,6). However, in contrast to Mc4r-null mice, energy expenditure is not reduced in Sim1 +/-mice, suggesting that the relationship between Sim1 and Mc4r is not a simple linear one (4,6).…”

“…Sim1 homozygous null mice (Sim1 -/-) die in the perinatal period and have abnormal hypothalamic architecture, lacking paraventricular, anterior periventricular, and supraoptic nuclei because of failure of terminal migration and differentiation of Sim1-expressing neurons (3). Sim1 heterozygous mice (Sim1 +/-) survive and develop severe obesity associated with increased food intake without any measurable deficit in energy expenditure, establishing a role for Sim1 in energy homeostasis (3)(4)(5). Conditional postnatal deletion of Sim1 in postmitotic neurons recapitulates the obesity phenotype seen in germline depletion of Sim1 in mice, indicating that Sim1 has a physiological role in energy homeostasis that is distinct from its role in hypothalamic development (6).…”

“…The obesity phenotype of Sim1 +/-mice closely resembles that of mice lacking the melanocortin 4 receptor (Mc4r) with increased linear growth and increased feeding efficiency in addition to an increase in food intake (3,4,6). However, in contrast to Mc4r-null mice, energy expenditure is not reduced in Sim1 +/-mice, suggesting that the relationship between Sim1 and Mc4r is not a simple linear one (4,6). Sim1 is expressed in the PVN, basomedial amygdala, anterior hypothalamus, and lateral hypothalamic area (5), regions that also have high concentrations of Mc4r-expressing neurons, and Mc4r mRNA levels in the PVN are significantly reduced in Sim1 +/-mice (6).…”

“…Sim1 is expressed in the PVN, basomedial amygdala, anterior hypothalamus, and lateral hypothalamic area (5), regions that also have high concentrations of Mc4r-expressing neurons, and Mc4r mRNA levels in the PVN are significantly reduced in Sim1 +/-mice (6). Administration of melanotan II, a potent melanocortin receptor agonist, results in a reduction in food intake in WT mice, whereas this response is blunted in Sim1 +/-mice, suggesting that Sim1 lies downstream of Mc4r (4). Transgenic overexpression of human SIM1 via a BAC transgene in Agouti mice (which ectopically overexpress the melanocortin receptor antagonist Agouti and share many of the features of Mc4r-null mice) ameliorates their phenotype by normalizing their food intake, suggesting that increased SIM1 expression is able to compensate for impaired Mc4r signaling (7).…”