Adenoviral-Mediated Modulation of<i>Sim1</i>Expression in the Paraventricular Nucleus Affects Food Intake

Yang, Chun; Gagnon, David; Vachon, Pascal; Tremblay, André; Lévy, Émile; Massie, Bernard; Michaud, Jacques L.

doi:10.1523/jneurosci.0672-06.2006

Cited by 40 publications

(43 citation statements)

References 17 publications

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“…Mouse models have shown Sim1 to play both a developmental and a postnatal physiological role in this nucleus (2-4, 6, 34), with evidence divided as to whether 1 functional copy of Sim1 is sufficient for its developmental function (4,35). Consistent with postnatal deletion of Sim1 causing hyperphagia (6), stereotaxic injection of an adenovirus expressing shRNA directed against Sim1 into the PVN has shown that reduction of Sim1 expression in a subset of neurons is sufficient to affect food intake (36) Ad libitum energy intake was increased in patients with SIM1 variants with no evidence of a defect in basal energy expenditure. SIM1 variant carriers had lower blood pressure measurements, showed an attenuated increase in heart rate on waking, and had increased respiratory quotients when compared with obese controls.…”

Section: Figurementioning

confidence: 99%

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

Ramachandrappa¹,

Raimondo²,

Cali³

et al. 2013

J. Clin. Invest.

144

113

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Single-minded 1 (SIM1) is a basic helix-loop-helix transcription factor involved in the development and function of the paraventricular nucleus of the hypothalamus. Obesity has been reported in Sim1 haploinsufficient mice and in a patient with a balanced translocation disrupting SIM1. We sequenced the coding region of SIM1 in 2,100 patients with severe, early onset obesity and in 1,680 controls. Thirteen different heterozygous variants in SIM1 were identified in 28 unrelated severely obese patients. Nine of the 13 variants significantly reduced the ability of SIM1 to activate a SIM1-responsive reporter gene when studied in stably transfected cells coexpressing the heterodimeric partners of SIM1 (ARNT or ARNT2). SIM1 variants with reduced activity cosegregated with obesity in extended family studies with variable penetrance. We studied the phenotype of patients carrying variants that exhibited reduced activity in vitro. Variant carriers exhibited increased ad libitum food intake at a test meal, normal basal metabolic rate, and evidence of autonomic dysfunction. Eleven of the 13 probands had evidence of a neurobehavioral phenotype. The phenotypic similarities between patients with SIM1 deficiency and melanocortin 4 receptor (MC4R) deficiency suggest that some of the effects of SIM1 deficiency on energy homeostasis are mediated by altered melanocortin signaling.

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Section: Figurementioning

confidence: 99%

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

Ramachandrappa¹,

Raimondo²,

Cali³

et al. 2013

J. Clin. Invest.

144

113

View full text Add to dashboard Cite

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“…Sim1-haploinsufficient mice display hypodevelopment of the paraventricular nucleus of the hypothalamus and are hyperphagic, obese, and highly sensitive to diet-induced obesity, whereas Sim1 overexpression in mice leads to a decrease in food intake (2)(3)(4). In humans, several deletions in the chromosome 6q16, the region that includes SIM1, have been identified in obese patients presenting with a Prader-Willi-like (PWL-like) syndrome (5), which is characterized in early infancy by global developmental delay, hypotonia, and feeding difficulties and later in life by hyperphagia, obesity, and facial dysmorphisms (6).…”

Section: Introductionmentioning

confidence: 99%

Loss-of-function mutations in SIM1 contribute to obesity and Prader-Willi–like features

Bonnefond

Raimondo²,

Stutzmann³

et al. 2013

J. Clin. Invest.

114

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Sim1 haploinsufficiency in mice induces hyperphagic obesity and developmental abnormalities of the brain. In humans, abnormalities in chromosome 6q16, a region that includes SIM1, were reported in obese children with a Prader-Willi-like syndrome; however, SIM1 involvement in obesity has never been conclusively demonstrated. Here, SIM1 was sequenced in 44 children with Prader-Willi-like syndrome features, 198 children with severe early-onset obesity, 568 morbidly obese adults, and 383 controls. We identified 4 rare variants (p.I128T, p.Q152E, p.R581G, and p.T714A) in 4 children with Prader-Willi-like syndrome features (including severe obesity) and 4 other rare variants (p.T46R, p.E62K, p.H323Y, and p.D740H) in 7 morbidly obese adults. By assessing the carriers' relatives, we found a significant contribution of SIM1 rare variants to intra-family risk for obesity. We then assessed functional effects of the 8 substitutions on SIM1 transcriptional activities in stable cell lines using luciferase gene reporter assays. Three mutations showed strong loss-of-function effects (p.T46R, p.H323Y, and p.T714A) and were associated with high intra-family risk for obesity, while the variants with mild or no effects on SIM1 activity were not associated with obesity within families. Our genetic and functional studies demonstrate a firm link between SIM1 loss of function and severe obesity associated with, or independent of, Prader-Willi-like features.

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“…Furthermore, transgenic overexpression of Sim1 conferred resistance to obesity induced either by HF diet or by the A y mutation that abrogates CNS Mc3r and Mc4r signaling (10). Moreover, Yang et al (11) showed that viral-mediated increase or decrease in Sim1 expression in the hypothalamus of adult mice acutely reduced or increased food intake, respectively. Finally, we used a neural-specific Cre transgene whose expression begins postnatally to conditionally inactivate Sim1 after birth, and showed that these mice develop hyperphagic obesity without loss of PVN neurons or gross alteration of hindbrain projections that are thought to mediate satiety (12).…”

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confidence: 99%

Inducible Neuronal Inactivation of Sim1 in Adult Mice Causes Hyperphagic Obesity

et al. 2014

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Germline haploinsufficiency of human or mouse Sim1 is associated with hyperphagic obesity. Sim1 encodes a transcription factor required for proper formation of the paraventricular (PVN), supraoptic, and anterior periventricular hypothalamic nuclei. Sim1 expression persists in these neurons in adult mice, raising the question of whether it plays a physiologic role in regulation of energy balance. We previously showed that Sim1 heterozygous mice had normal numbers of PVN neurons that were hyporesponsive to melanocortin 4 receptor agonism and showed reduced oxytocin expression. Furthermore, conditional postnatal neuronal inactivation of Sim1 also caused hyperphagic obesity and decreased hypothalamic oxytocin expression. PVN projections to the hindbrain, where oxytocin is thought to act to modulate satiety, were anatomically intact in both Sim1 heterozygous and conditional knockout mice. These experiments provided evidence that Sim1 functions in energy balance apart from its role in hypothalamic development but did not rule out effects of Sim1 deficiency on postnatal hypothalamic maturation. To address this possibility, we used a tamoxifen-inducible, neural-specific Cre transgene to conditionally inactivate Sim1 in adult mice with mature hypothalamic circuitry. Induced Sim1 inactivation caused increased food and water intake and decreased expression of PVN neuropeptides, especially oxytocin and vasopressin, with no change in energy expenditure. Sim1 expression was not required for survival of PVN neurons. The results corroborate previous evidence that Sim1 acts physiologically as well as developmentally to regulate body weight. Inducible knockout mice provide a system for studying Sim1's physiologic function in energy balance and identifying its relevant transcriptional targets in the hypothalamus. (Endocrinology 155: 2436 -2444, 2014) T he mouse Single-minded homolog 1 (Sim1) gene encodes a member of the bHLH-PAS family of nuclear transcription factors and is expressed during embryogenesis in developing somites, nephrogenic cord, foregut, and forebrain (1, 2). Sim1 expression is required for terminal migration and differentiation of the neurons of the paraventricular (PVN), supraoptic (SON), and anterior periventricular (aPV) nuclei of the hypothalamus, which produce the neuroendocrine peptides oxytocin, arginine vasopressin, corticotropin-releasing hormone, thyrotropin-releasing hormone, and somatostatin. Sim1 continues to be expressed in neurons of these nuclei, as well as in the amygdala, in adult mice. Its transcriptional target genes are not known. We hypothesized a role for Sim1 in energy homeostasis after discovering that cytogenetic abnormalities disrupting one allele of the orthologous human SIM1 gene were associated with early-onset, severe obesity (3). This hypothesis was confirmed by the phenotype of Sim1 heterozygous knockout mice, which includes hyperphagic obesity exacerbated by high fat (HF) diet (4, 5), as well as the finding of rare human SIM1 loss-of-function missense mutations associated with hy...

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

Cited by 40 publications

References 17 publications

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

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

Loss-of-function mutations in SIM1 contribute to obesity and Prader-Willi–like features

Inducible Neuronal Inactivation of Sim1 in Adult Mice Causes Hyperphagic Obesity

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