The Wnt pathway elicits a signalling cascade involving the effector molecule β-catenin and the transcription factor TCF7L2, the latter identified to be genetically associated with the pathogenesis of obesity and type-2 diabetes. Here, we sought to determine whether β-catenin plays an important role in the neuroendocrine regulation of body weight and glucose homeostasis. Using male and female β-cateninflox mice, we performed bilateral injections of AAV2-mCherry-Cre into the arcuate nucleus to specifically delete β-catenin expression in that region in adult mice (MBH-β-cat KO). Surprisingly, on low-fat diet, MBH-β-cat KO mice were no different in body weight, despite equal caloric intake but markedly increased energy expenditure (P<0.05). Nonetheless, the mice did exhibit impaired glucose clearance (P<0.05). On high-fat diet, despite only a small difference in weekly caloric intake (P<0.05), the MBH-β-cat KO mice were markedly heavier than the control mice (P<0.05). This deficit seems to be a failure to show adaptive increase in energy expenditure seen in control animal that served to offset the increased calories by HFD. Again, both male and female mice had impaired glucose clearance, with the MBH-β-cat KO mice being highly glucose intolerant compared to control mice (P<0.05). Male MBH-β-cat KO mice displayed a significant reduction in both leptin and insulin sensitivity compared with control mice (P<0.05), but this effect was less pronounced in the females. This study highlights a critical role for β-catenin in the hypothalamic circuits regulating body weight and glucose homeostasis and reveals mechanisms by which genetic alterations in this pathway could impact on development of metabolic disease.