Here, we present data showing that while ActRIIA/IIB blockade holds promise for enhancing muscle mass, function, and insulin sensitivity, it also induces severe glucose intolerance, hepatic steatosis, and reduces voluntary physical activity in mice, underscoring the complex metabolic and functional consequences of ActRIIA/IIB blockade and highlighting the importance of delineating species differences with these potential therapeutics. The gene discussed is ACVR2A; the disease is Hepatic steatosis.