Biology subjects

Xu, P. W.

Publications and source records attributed to Xu, P. W..

3 recordsLinked to original sources

bioRxiv2025

Protection against diet-induced obesity by a single-point mutation in Kir2.1 channels

High-fat diet (HFD)-induced obesity remains a significant global health challenge. In this study, we show that a global knock-in CRISPR mouse with the Kir2.1L222I single-point mutation exhibits remarkable resistance to HFD-induced obesity. We identify palmitic acid (PA), a prevalent long-chain fatty acid in obesity, as a novel negative regulator of Kir2.1. Kir2.1L222I previously shown to protect against cholesterol-mediated inhibition of Kir2.1, also confers protection against PA-induced suppression. Moreover, PA-induced suppression of Kir2.1 results in a significant loss of flow-induced vasodilation (FIV), while the L222I mutation exerts a protective effect. Notably, Kir2.1L222I mice display significant protection against HFD-induced weight gain and adiposity independent of caloric intake. Specifically, the mutant mice show increased lean mass and decreased fat mass, specifically in both visceral and subcutaneous white adipose tissue (WAT) and intrascapular brown adipose tissue (BAT). Importantly, visceral-to-subcutaneous white adipose ratios decrease while BAT/WAT tissue ratios increase, suggesting a metabolically favorable fat distribution. This protection correlates with enhanced physical activity and increased energy expenditure. Metabolomic analysis reveals elevated TCA cycle metabolites in adipose tissue of Kir2.1L222I mice, consistent with their enhanced energy expenditure. These findings highlight Kir2.1 channels as potential therapeutic targets for obesity and related metabolic disorders.

physiology↗

bioRxiv2023

Estrogen prevents age-dependent beige adipogenesis failure through NAMPT-controlled ER stress pathway

Thermogenic beige adipocytes are recognized as potential therapeutic targets for combating metabolic diseases. However, the metabolic advantages they offer are compromised with aging. Here, we show that treating mice with estrogen (E2), a hormone that decreases with age, to mice can counteract the aging- related decline in beige adipocyte formation when subjected to cold, while concurrently enhancing energy expenditure and improving glucose tolerance. Mechanistically, we find that nicotinamide phosphoribosyltranferase (NAMPT) plays a pivotal role in facilitating the formation of E2-induced beige adipocytes, which subsequently suppresses the onset of age-related ER stress. Furthermore, we found that targeting NAMPT signaling, either genetically or pharmacologically, can restore the formation of beige adipocytes by increasing the number of perivascular adipocyte progenitor cells. Conversely, the absence of NAMPT signaling prevents this process. In conclusion, our findings shed light on the mechanisms governing the age-dependent impairment of beige adipocyte formation and underscore the E2-NAMPT controlled ER stress as a key regulator of this process. HighlightsO_LIEstrogen restores beige adipocyte failure along with improved energy metabolism in old mice. C_LIO_LIEstrogen enhances the thermogenic gene program by mitigating age-induced ER stress. C_LIO_LIEstrogen enhances the beige adipogenesis derived from SMA+ APCs. C_LIO_LIInhibiting the NAMPT signaling pathway abolishes estrogen-promoted beige adipogenesis. C_LI

physiology↗

bioRxiv2019

α-ketoglutaric acid stimulates muscle hypertrophy and fat loss through OXGR1-dependent adrenal activation

Beneficial effects of resistance exercise on metabolic health and particularly muscle hypertrophy and fat loss are well established, but the underlying chemical and physiological mechanisms are not fully understood. Here we identified a myometabolite-mediated metabolic pathway that is essential for the beneficial metabolic effects of resistance exercise in vivo. We showed that substantial accumulation of the tricarboxylic acid cycle intermediate -ketoglutaric acid (AKG) is a metabolic signature of resistance exercise performance. Interestingly, human plasma AKG level is also negatively correlated with BMI. Pharmacological elevation of circulating AKG induces muscle hypertrophy, brown adipose tissue (BAT) thermogenesis, and white adipose tissue (WAT) lipolysis in vivo. We further found that AKG stimulates the adrenal release of adrenaline through 2-oxoglutarate receptor 1 (OXGR1) expressed in adrenal glands. Finally, by using both loss-of-function and gain-of-function mouse models, we showed that OXGR1 is essential for AKG-mediated exercise-induced beneficial metabolic effects. These findings reveal an unappreciated mechanism for the salutary effects of resistance exercise, using AKG as a systemically-derived molecule for adrenal stimulation of muscle hypertrophy and fat loss.

molecular biology↗