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BACKGROUND The consumption of large amounts of dietary fats induces hypothalamic inflammation and impairs the function of the melanocortin system, leading to a defective regulation of caloric intake and whole-body energy expenditure. In mice fed a high-fat diet (HFD), TGF-β1 expression was increased and NF-κB signaling was activated in proopiomelanocortin neurons, which plays an important role in the obesity-associated hypothalamic inflammation scenario. However, whether excessive hypothalamic TGF-β1 impairs energy homeostasis remains unclear. OBJECTIVES We aimed to investigate the role of diet-induced hypothalamic TGF-β1 on inflammation and whole-body energy homeostasis. METHODS A TGF-β1 inhibitory lentiviral shRNA particle was stereotaxically injected bilaterally in the arcuate nucleus (ARC) of C57BL/6 mice fed a HFD. We assessed changes in body mass and adiposity, food intake, inflammatory markers, and the function of energy and glucose metabolism. RESULTS TGF-β1 down-regulation in the ARC-attenuated body-mass gain, reduced fat-mass accumulation, decreased hypothalamic inflammatory markers, and protected against HFD-induced lipohypertrophy of brown adipose tissue. In addition, the inhibition of hypothalamic TGF-β1 increased the locomotor activity and improved whole-body lipid metabolism, which attenuated hepatic fat accumulation and serum triglyceride levels. No changes were observed in food intake and glucose homeostasis. CONCLUSION Hypothalamic TGF-β1 down-regulation attenuates hypothalamic inflammation and improves energy metabolism, resulting in lower body-mass gain and lower fat-mass accumulation, which protects mice from the development of obesity. Our data suggest that modulation of hypothalamic TGF-β1 expression might be an effective strategy to treat obesity.