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Obesity affects a significant fraction of the world population, with some states or countries reporting overwhelming majority of the population as obese or overweight. Effective treatments were not readily available until the recent approval of glucagon-like peptide-1 (GLP-1) -based pharmacotherapeutics for weight loss. Since then, the use of GLP-1-based pharmacotherapies for the treatment of obesity has skyrocketed. In addition to or because of the effective weight loss, these medications affect many different organs in the body. Many of these effects, including the degree of weight loss achieved, show significant sex differences. Moreover, recent analysis of online patient communities identified a range of self-reported reproductive and endocrine side effects of GLP-1 based therapies including menstrual irregularities, reduced libido, and hot-flashes that have not been systematically captured in clinical trials. Some of these reports contrast with recent data indicating that in Polyendocrine Metabolic Ovarian Syndrome (PMOS; formerly Polycystic Ovary Syndrome) patients semaglutide-associated weight loss normalizes menstrual cycles in most patients, leaving this issue unresolved. While it has been established that sex and sex hormones affect the action of GLP-1 analogues, whether these medications affect the levels of sex hormones and reproductive organs is less well understood, especially in a chronic and clinically relevant drug application setting.

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Roles for Leptin Receptor Transcriptional Targets in the Control of Body Weight

Cagri Bodur, Sandra Attisha, Allison Duensing, Abigail Tomlinson, ... Martin G. Myers

The adipose-derived hormone leptin activates the signaling isoform of the leptin receptor (LepRb) on hypothalamic neurons to signal the repletion of energy stores, thereby restraining food intake and body weight. LepRb is a type 1 cytokine receptor whose activation of the transcription factor, STAT3, plays a crucial role in the restraint of food intake and body weight. Hence, the transcriptional targets of LepRb must contribute importantly to leptin action. Our previous analysis of gene expression in hypothalamic Lepr neurons identified several genes that are enriched and consistently leptin-regulated in these cells, including Irf9, Asb4, and Serpina3n. To define potential roles for these genes in the control of energy balance, we deleted them in Lepr neurons (using LeprCre) or across the hypothalamus (using Nkx2.1Cre). Ablating Irf9 or Serpina3n failed to alter body weight or adiposity. In contrast, deleting Asb4 in Lepr neurons increased food intake, body weight, and adiposity, with a tendency toward a larger effect in females. Furthermore, ablating Asb4 throughout the hypothalamus augmented this phenotype. Hence, while Irf9 and Serpina3n in Lepr neurons are dispensable for the control of energy balance, Asb4 expression in Lepr neurons plays a role in the regulation of body weight. Because the loss of Asb4 throughout the hypothalamus further increases obesity, this gene must play Lepr neuron-independent as well as leptin-mediated roles in energy balance.

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Roles for Leptin Receptor Transcriptional Targets in the Control of Body Weight

Cagri Bodur, Sandra Attisha, Allison Duensing, Abigail Tomlinson, ... Martin G. Myers

The adipose-derived hormone leptin activates the signaling isoform of the leptin receptor (LepRb) on hypothalamic neurons to signal the repletion of energy stores, thereby restraining food intake and body weight. LepRb is a type 1 cytokine receptor whose activation of the transcription factor, STAT3, plays a crucial role in the restraint of food intake and body weight. Hence, the transcriptional targets of LepRb must contribute importantly to leptin action. Our previous analysis of gene expression in hypothalamic Lepr neurons identified several genes that are enriched and consistently leptin-regulated in these cells, including Irf9, Asb4, and Serpina3n. To define potential roles for these genes in the control of energy balance, we deleted them in Lepr neurons (using LeprCre) or across the hypothalamus (using Nkx2.1Cre). Ablating Irf9 or Serpina3n failed to alter body weight or adiposity. In contrast, deleting Asb4 in Lepr neurons increased food intake, body weight, and adiposity, with a tendency toward a larger effect in females. Furthermore, ablating Asb4 throughout the hypothalamus augmented this phenotype. Hence, while Irf9 and Serpina3n in Lepr neurons are dispensable for the control of energy balance, Asb4 expression in Lepr neurons plays a role in the regulation of body weight. Because the loss of Asb4 throughout the hypothalamus further increases obesity, this gene must play Lepr neuron-independent as well as leptin-mediated roles in energy balance.

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