The Role of PPARβ/δ-Related Lipid Metabolism in High-Altitude Adaptation of Yak Coat Based on Proteomics and Metabolomics

<b>Background:</b> In the cold plateau environment, the yak's coat exhibits significant adaptive regulation to cope with adverse conditions. This adaptation is fundamentally governed by the cycle of hair follicles (HFs), a complex process involving numerous molecular signals. However, the key regulators and underlying pathways remain poorly understood. <b>Methods:</b> Proteomic and non-targeted metabolomic analyses were employed to systematically investigate changes in proteins and metabolites during the cycle of yak hair follicles. We further validated the expression dynamics of PPARβ/δ and its related molecules, as well as the specific biological role of PPARβ/δ in regulating lipid metabolism and influencing the proliferation and apoptosis of yak dermal papilla cells (DPCs). <b>Results:</b> Proteomic results indicated that lipid-related proteins were among the most significantly altered, second only to hair structural proteins. The PPAR signaling pathway, which regulates lipid metabolism, may also play an important role in the cycle of yak HF. Non-targeted metabolomics revealed that Fatty Acyls were the most significantly altered metabolites during the transitions into anagen and catagen. Notably, unsaturated long-chain fatty acids (PPARβ/δ agonists) were consistently up-regulated in anagen and down-regulated in catagen, whereas saturated long-chain fatty acids (lacking PPARβ/δ agonist activity) did not exhibit a similar trend. PPARβ/δ shows significant expression changes in the dermal papilla (DP) and hair matrix (HM) during the cycle of yak HFs. Specifically, PPARβ/δ expression in the DP underwent progressive downregulation during the transition from anagen to catagen and subsequently to telogen, becoming nearly undetectable in the telogen DP. Cellular experiments confirmed that PPARβ/δ activation significantly reduced intracellular lipid content in yak DPCs and was accompanied by increased proliferation. Conversely, PPARβ/δ inhibition led to intracellular lipid accumulation and decreased proliferation. <b>Conclusions:</b> These findings suggest that PPARβ/δ may regulate the yak HF cycle by modulating lipid metabolism in DP. The level of intrinsic lipid metabolism within HFs may be a key factor influencing yak HF growth.