Biology subjects

Zhou, E. Y.

Publications and source records attributed to Zhou, E. Y..

2 recordsLinked to original sources

bioRxiv2026

GDF3 is an endogenous antagonist of the ActE-ALK7/ACVR2 pathway in adipocytes

Metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) arise, in part, from excessive free fatty acid flux from adipose tissue to the liver. Activin E (ActE, encoded by INHBE) suppresses adipocyte lipolysis through the type I receptor ALK7 (ACVR1C). Loss-of-function variants in INHBE and ACVR1C reduce waist-to-hip ratio in humans, yet genetic knockouts in mice produce insulin resistance and hepatic steatosis, suggesting discrepancies between human and mouse biology. We identify GDF3, a TGF-{beta} superfamily ligand upregulated in obese adipose tissue, as the principal endogenous antagonist of ActE/ALK7 signaling. Human transcriptomic datasets reveal coordinated dysregulation: hepatic INHBE expression and circulating ActE protein are elevated in obesity, while adipose ACVR1C is downregulated and GDF3 is reciprocally upregulated. Using ALK7-selective reporter assays, we show GDF3 inhibits ActE-driven SMAD2/3 signaling as a competitive antagonist rather than the weak agonist previously proposed. ActE suppressed beta-adrenergic-stimulated lipolysis in mouse and human adipocytes and primary human adipose tissue; GDF3 overexpression abolished this effect. In diet-induced obese mice, inducible Gdf3 deletion reduced adipose lipolysis, resolved hepatic steatosis and fibrosis, and improved insulin sensitivity, benefits abolished by Inhbe knockdown, confirming dependence on ActE signaling. Predicted loss-of-function variants in INHBE show only nominal, WHR-dependent associations with type 2 diabetes risk, potentially confounded by hematological effects on HbA1c. Gdf3 deficiency synergized with the clinical-stage anti-activin receptor antibody Bimagrumab to amplify fat-mass loss and improve glucose homeostasis in multiple MASH models. These findings establish GDF3 as an endogenous antagonist of ActE-ALK7 signaling and nominate GDF3 inhibition as a therapeutic strategy for MASLD/MASH.

physiology↗

bioRxiv2026

Metabolic responses to physiological stressors assessed using continuous glucose monitoring integrated with indirect calorimetry in mice

Continuous glucose monitoring (CGM) in rodents has provided unprecedented temporal resolution of glycemic dynamics in vivo. Even in the absence of deliberate perturbation, glucose levels in mice are dynamic, fluctuating in response to the timing and duration of feeding events, changes in neurological and hormonal states, physical activity, and photoperiod. To obtain a comprehensive view of metabolic adaptations under common experimental conditions, we monitored freely moving mice simultaneously using CGM and indirect calorimetry to quantify glucose, food intake, physical activity and metabolic rate. We characterized glycemic and metabolic responses to routine laboratory interventions, including short-term and overnight fasting, refeeding, tail blood sampling during glucose tolerance tests, changes in ambient temperature to cold or thermoneutral conditions, and access to running wheels. We found that food removal induced a robust, transient stress response characterized by increased blood glucose, body temperature, energy expenditure, and physical activity. However, prolonged fasting ultimately led to hypoglycemia and torpor. The magnitude and variability of glycemic responses to insulin tolerance tests were strongly influenced by fasting duration, and tail-tip blood collection itself elicited substantial hyperglycemia. In contrast to prolonged fasting, refeeding produced relatively modest and transient effects on glucose and energy expenditure. Cold exposure elicited increased energy expenditure along with a sustained hyperglycemic response. Voluntary wheel running induced transient increases in glucose and metabolic activity and promoted a shift toward increased fatty acid oxidation. Together, these findings demonstrate that common laboratory manipulations exert dynamic, often substantial effects on glycemia and whole-body metabolism that are readily revealed by CGM and indirect calorimetry.

physiology↗