6 research outputs found
Thyroid Hormone Receptor Beta in the Ventromedial Hypothalamus Is Essential for the Physiological Regulation of Food Intake and Body Weight.
The obesity epidemic is a significant global health issue. Improved understanding of the mechanisms that regulate appetite and body weight will provide the rationale for the design of anti-obesity therapies. Thyroid hormones play a key role in metabolic homeostasis through their interaction with thyroid hormone receptors (TRs), which function as ligand-inducible transcription factors. The TR-beta isoform (TRβ) is expressed in the ventromedial hypothalamus (VMH), a brain area important for control of energy homeostasis. Here, we report that selective knockdown of TRβ in the VMH of adult mice results in severe obesity due to hyperphagia and reduced energy expenditure. The observed increase in body weight is of a similar magnitude to murine models of the most extreme forms of monogenic obesity. These data identify TRβ in the VMH as a major physiological regulator of food intake and energy homeostasis
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Heterogeneity of hypothalamic pro-opiomelanocortin-expressing neurons revealed by single-cell RNA sequencing
Arcuate proopiomelanocortin (POMC) neurons are critical nodes in the control of body weight. Often characterized simply as direct targets for leptin, recent data suggest a more complex architecture.
Using single cell RNA sequencing, we have generated an atlas of gene expression in murine POMC neurons.
Of 163 neurons, 118 expressed high levels of with little/no Agrp expression and were considered “canonical” POMC neurons (P). The other 45/163 expressed low levels of and high levels of (AP). Unbiased clustering analysis of P neurons revealed four different classes, each with distinct cell surface receptor gene expression profiles. Further, only 12% (14/118) of P neurons expressed the leptin receptor () compared with 58% (26/45) of AP neurons. In contrast, the insulin receptor () was expressed at similar frequency on P and AP neurons (64% and 55%, respectively).
These data reveal arcuate POMC neurons to be a highly heterogeneous population. Accession Numbers: GSE92707.This work was supported by the UK Medical Research Council (MRC) Metabolic Disease Unit (MRC_MC_UU_12012/1 & MRC_MC_UU_12012/5), a Wellcome Trust Strategic Award (100574/Z/12/Z), and the Helmholtz Alliance ICEMED
Heterogeneity of hypothalamic pro-opiomelanocortin-expressing neurons revealed by single-cell RNA sequencing
Arcuate proopiomelanocortin (POMC) neurons are critical nodes in the control of body weight. Often characterized simply as direct targets for leptin, recent data suggest a more complex architecture.
Using single cell RNA sequencing, we have generated an atlas of gene expression in murine POMC neurons.
Of 163 neurons, 118 expressed high levels of with little/no Agrp expression and were considered “canonical” POMC neurons (P). The other 45/163 expressed low levels of and high levels of (AP). Unbiased clustering analysis of P neurons revealed four different classes, each with distinct cell surface receptor gene expression profiles. Further, only 12% (14/118) of P neurons expressed the leptin receptor () compared with 58% (26/45) of AP neurons. In contrast, the insulin receptor () was expressed at similar frequency on P and AP neurons (64% and 55%, respectively).
These data reveal arcuate POMC neurons to be a highly heterogeneous population. Accession Numbers: GSE92707.This work was supported by the UK Medical Research Council (MRC) Metabolic Disease Unit (MRC_MC_UU_12012/1 & MRC_MC_UU_12012/5), a Wellcome Trust Strategic Award (100574/Z/12/Z), and the Helmholtz Alliance ICEMED
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The obesity-associated gene TMEM18 has a role in the central control of appetite and body weight regulation
An intergenic region of human chromosome 2 (2p25.3) harbors genetic variants which are among those most strongly and reproducibly associated with obesity. The gene closest to these variants is TMEM18, although the molecular mechanisms mediating these effects remain entirely unknown. Tmem18 expression in the murine hypothalamic paraventricular nucleus (PVN) was altered by changes in nutritional state. Germline loss of Tmem18 in mice resulted in increased body weight, which was exacerbated by high fat diet and driven by increased food intake. Selective overexpression of Tmem18 in the PVN of wild-type mice reduced food intake and also increased energy expenditure. We provide evidence that TMEM18 has four, not three, transmembrane domains and that it physically interacts with key components of the nuclear pore complex. Our data support the hypothesis that TMEM18 itself, acting within the central nervous system, is a plausible mediator of the impact of adjacent genetic variation on human adiposity.RL, YCLT, DR, GSHY, SOR and APC are funded by the Medical Research Council (MRC) Metabolic Disease Unit (MRC_MC_UU_12012/1) and animal work was carried out with the assistance of MRC Disease Model Core of the Wellcome Trust MRC Institute of Metabolic Sciences (MRC_MC_UU_12012/5 and Wellcome Trust Strategic Award (100574/Z/12/Z). F. Bosch is the recipient of an award from the ICREA Academia, Generalitat de Catalunya, Spain. Vector generation and production were funded by Ministerio de EconomĂa y Competitividad (SAF 2014-54866-R), Spain. CD and DWL were supported by the Wellcome Trust (WT098051) and CD was supported by the Wellcome Trust PhD Programme for Clinicians (100679/Z/12/Z)
SNORD116 and growth hormone therapy impact IGFBP7 in Prader–Willi syndrome
International audiencePurpose: Prader-Willi syndrome (PWS) is a neurodevelopmental disorder with hypothalamic dysfunction due to deficiency of imprinted genes located on the 15q11-q13 chromosome. Among them, the SNORD116 gene appears critical for the expression of the PWS phenotype. We aimed to clarify the role of SNORD116 in cellular and animal models with regard to growth hormone therapy (GHT), the main approved treatment for PWS.Methods: We collected serum and induced pluripotent stem cells (iPSCs) from GH-treated PWS patients to differentiate into dopaminergic neurons, and in parallel used a Snord116 knockout mouse model. We analyzed the expression of factors potentially linked to GH responsiveness.Results: We found elevated levels of circulating IGFBP7 in naive PWS patients, with IGFBP7 levels normalizing under GHT. We found elevated IGFBP7 levels in the brains of Snord116 knockout mice and in iPSC-derived neurons from a SNORD116-deleted PWS patient. High circulating levels of IGFBP7 in PWS patients may result from both increased IGFBP7 expression and decreased IGFBP7 cleavage, by downregulation of the proconvertase PC1.Conclusion: SNORD116 deletion affects IGFBP7 levels, while IGFBP7 decreases under GHT in PWS patients. Modulation of the IGFBP7 level, which interacts with IGF1, has implications in the pathophysiology and management of PWS under GHT