1. BRS3 in both MC4R- and SIM1-expressing neurons regulates energy homeostasis in mice
Ramón A Piñol, Marc L Reitman, Haley Province, Naili Liu, Oksana Gavrilova, Cuiying Xiao Mol Metab . 2020 Jun;36:100969. doi: 10.1016/j.molmet.2020.02.012.
Objective:Bombesin-like receptor 3 (BRS3) is an orphan receptor and Brs3 knockout mice develop obesity with increased food intake and reduced resting metabolic rate and body temperature. The neuronal populations contributing to these effects were examined.Methods:We studied energy metabolism in mice with Cre-mediated recombination causing 1) loss of BRS3 selectively in SIM1- or MC4R-expressing neurons or 2) selective re-expression of BRS3 from a null background in these neurons.Results:The deletion of BRS3 in MC4R neurons increased body weight/adiposity, metabolic efficiency, and food intake, and reduced insulin sensitivity. BRS3 re-expression in these neurons caused partial or no reversal of these traits. However, these observations were confounded by an obesity phenotype caused by the Mc4r-Cre allele, independent of its recombinase activity. The deletion of BRS3 in SIM1 neurons increased body weight/adiposity and food intake, but not to the levels of the global null. The re-expression of BRS3 in SIM1 neurons reduced body weight/adiposity and food intake, but not to wild type levels. The deletion of BRS3 in either MC4R- or SIM1-expressing neurons affected body temperature, with re-expression in either population reversing the null phenotype. MK-5046, a BRS3 agonist, increases light phase body temperature in wild type, but not Brs3 null, mice and BRS3 re-expression in either population restored response to MK-5046.Conclusions:BRS3 in both MC4R- and SIM1-expressing neurons contributes to regulation of body weight/adiposity, insulin sensitivity, food intake, and body temperature.
2. Ectopic expression of Irx3 and Irx5 in the paraventricular nucleus of the hypothalamus contributes to defects in Sim1 haploinsufficiency
Jade Chan, Joe Eun Son, Xi Huang, Xuejun Li, Jacques L Michaud, Zhengchao Dou, Kyoung-Han Kim, Chi-Chung Hui, Siyi Wanggou, Rong Mo Sci Adv . 2021 Oct 29;7(44):eabh4503. doi: 10.1126/sciadv.abh4503.
The paraventricular nucleus of the hypothalamus (PVH) contains a heterogeneous cluster ofSim1-expressing neurons critical for feeding regulation.Sim1haploinsufficiency results in hyperphagic obesity with disruption of PVH neurons, yet the molecular profiles of PVH neurons and the mechanism underlying the defects ofSim1haploinsufficiency are not well understood. By single-cell RNA sequencing, we identified two major populations ofSim1+PVH neurons, which are differentially affected bySim1haploinsufficiency. TheIroquoishomeobox genesIrx3andIrx5have been implicated in the hypothalamic control of energy homeostasis. We found thatIrx3andIrx5are ectopically expressed in theSim1+PVH cells ofSim1+/-mice. By reducing their dosage and PVH-specific deletion ofIrx3, we demonstrate that misexpression ofIrx3andIrx5contributes to the defects ofSim1+/-mice. Our results illustrate abnormal hypothalamic activities ofIrx3andIrx5as a central mechanism disrupting PVH development and feeding regulation inSim1haploinsufficiency.
3. Functional Analysis of the SIM1 Variant p.G715V in 2 Patients With Obesity
Mieke M van Haelst, Owen A Ross, Jay A van Gerpen, Patrick R Blackburn, Alexis G Gerassimou, Mellody Cooiman, Klaas J Wierenga, Paldeep S Atwal, Thomas R Caulfield, Eric W Klee, Murray L Whitelaw, Kimberly G Harris, Adrienne E Sullivan, David C Bersten, Lotte Kleinendorst J Clin Endocrinol Metab . 2020 Jan 1;105(1):dgz192. doi: 10.1210/clinem/dgz192.
Context:Single-minded homologue 1 (SIM1) is a transcription factor with several physiological and developmental functions. Haploinsufficiency of SIM1 is associated with early-onset obesity with or without Prader-Willi-like (PWL) features and may exhibit incomplete penetrance.Case description:Next-generation sequencing was performed for 2 male patients with obesity, including 1 man presenting with intellectual disability (ID), body mass index (BMI) of 47.4, and impulse-control disorder, and the other man with early obesity (BMI of 36); sequencing revealed a missense variant in SIM1 (c.2144G>T; p.G715V) in both individuals. Previous studies have identified several disease-associated variants that fall near the p.G715V variant within the C-terminal domain of SIM1. We examined p.G715V variant stability and activity in a doxycycline-inducible stable cell line transfected with an artificial reporter construct and either ARNT or ARNT2 as a partner protein.Conclusions:Functional testing of the p.G715V variant revealed a significant reduction in SIM1-mediated transcriptional activity. We also generated the first ab initio hybrid protein model for full-length SIM1 to show the predicted spatial relationship between p.G715V and other previously described variants in this region and identified a putative mutation hotspot within the C-terminus. Significant clinical heterogeneity has been observed in patients with SIM1 variants, particularly with regards to the PWL phenotype. In the patient with ID, a second variant of uncertain significance in CHD2 was identified that may contribute to his ID and behavioral disturbances, emphasizing the role of additional genetic modifiers.
