CTRP6–AdipoR1 signaling promotes testosterone production and alleviates obesity-associated male reproductive dysfunction

Obesity is a major risk factor for male infertility, yet the molecular mechanisms linking obesity to impaired spermatogenesis remain poorly defined. Here we show that C1q/TNF-related protein 6 (CTRP6) is a Leydig cell-derived regulator of testosterone production whose local expression is reduced in obesity. High-fat diet (HFD) feeding selectively reduced CTRP6 expression and secretion in Leydig cells despite elevated circulating CTRP6 levels, indicating tissue-specific dysregulation within the testicular microenvironment. Leydig cell-specific CTRP6 overexpression markedly alleviated HFD-induced testicular atrophy, restored seminiferous tubule architecture, improved sperm parameters and reproductive outcomes, and rescued testosterone production. Conversely, Leydig cell-specific CTRP6 knockout impaired spermatogenesis and reduced male reproductive capacity under normal-diet conditions, supporting an important role for endogenous CTRP6 in reproductive homeostasis. The combined secretion, genetic and extracellular-protein experiments are consistent with an autocrine contribution. Transcriptomic analyses identified CYP51A1 as a candidate downstream mediator. CTRP6 associated with adiponectin receptor 1 (AdipoR1), and AdipoR1 knockdown attenuated rhCTRP6-associated changes in PI3K/Akt phosphorylation, SREBP2 and CYP51A1 abundance, cholesterol content and testosterone production. Notably, intratesticular administration of recombinant human CTRP6 (rhCTRP6) effectively rescued HFD-induced spermatogenic dysfunction in vivo. Together, these findings uncover a previously unrecognized local Leydig cell-derived CTRP6 signaling model linking obesity to male reproductive dysfunction.