SAT-159 Transcriptomic Profiling Of Kiss1Arc Neurons Reveals Novel Mechanisms For Male Obesity-induced Hypogonadism

Abstract Disclosure: V. Sobrino: None. M. Jimenez-Puyer: None. A. Barroso-Romero: None. M. Mora-Ortiz: None. S. Arroyo-Moreno: None. C. Perdices-Lopez: None. F. Ruiz-Pino: None. M. Ruiz-Cruz: None. M. Avendaño: None. M. Tena-Sempere: None. Among its multiple co-morbidities, obesity is frequently linked to central hypogonadism, observed in up to 50% of men with severe obesity. This often overlooked condition of male obesity-induced hypogonadism (MOIH) can have not only sexual and reproductive implications, but may contribute also to exacerbate the metabolic complications of obesity along the lifespan. Kiss1 neurons in the arcuate nucleus of the hypothalamus (Kiss1ARC) play a fundamental role in the regulation of the reproductive axis and its modulation of energy and metabolic signals. Previous data have shown a suppression of Kiss1 expression in Kiss1ARC neurons in conditions of MOIH. Yet, more integral assessment of molecular changes in this key neuronal population in long-term obesity is missing. We report here global transcriptomic changes in Kiss1ARC neurons in a mouse model of MOIH. Male Kiss1::tdTomato mice were exposed to an obesogenic environment postnatally, by feeding lactating dams with high-fat diet (HFD), followed by HFD after weaning. At five months of age, the animals were subjected to metabolic and hormonal phenotyping and tdTomato-tagged Kiss1ARC neurons isolated using FACS for bulk RNA-seq. Obese mice displayed early-onset obesity, linked to increased adiposity, basal hyperglycemia, glucose intolerance and insulin resistance, which was associated with consistent suppression of circulating LH levels, as surrogate marker of central hypogonadism. Direct qPCR analyses confirmed suppression of Kiss1 expression in isolated Kiss1ARC neurons from MOIH mice, despite invariant expression of Tac2 (encoding NKB) and Pdyn (encoding dynorphin). Transcriptomic profiling revealed large sets of differentially expressed genes in Kiss1ARC neurons from MOIH mice, which allowed perfect clustering and discrimination vs. controls. Among different biological pathways, this molecular fingerprint pointed towards a remodeling of the perineuronal net caused by early-onset obesity specifically in Kiss1ARC neurons, affecting both their extracellular matrix and synaptic components. These global changes can lead to reorganization of the Kiss1ARC neuronal connectome, as major putative mechanism for the state of central hypogonadism in conditions of obesity. Presentation: Saturday, July 12, 2025