The brain influences liver metabolism through many neuroendocrine and autonomic mechanisms that have evolved to protect the organism against starvation and hypoglycemia. Unfortunately, these sophisticated homeostatic processes can be impaired in metabolic diseases such as obesity and type 2 diabetes, where autonomic dysfunctions have been described. However, the precise mechanisms by which the brain regulates hepatic metabolism, how autonomic dysfunctions can alter brain-liver communication, and whether alterations in the autonomic outflow to the liver contribute to hyperglycemia, remain to be defined. Based on recent studies convincingly showing that neural innervations within the liver are of sympathetic nature, we hypothesized that adrenergic receptors expressed by hepatocytes directly mediate the autonomic control of liver metabolism and can be pharmacologically targeted in metabolic diseases. Confirming a previous anatomical profiling study of GPCR expression, we observed that the adrenoceptor alpha-1b (Adra1b) was the dominant subtype expressed in the liver. We found that Adra1b expression was increased in diet-induced or genetically obese mouse models. Using CRISPR-Cas9 technology, we developed a conditional mouse model for the Adra1b gene. These mice were bred with an Albumin-Cre mouse to generate mice lacking Adra1b specifically in hepatocytes. We found that selective deletion of Adra1b in mouse liver reduced the ability of norepinephrine to cause hyperglycemia. We also found that mice lacking Adra1b in the liver were not able to maintain their glycemia during metabolically challenging conditions. Our data suggest that ADRA1B is key in mediating the effects of the autonomic nervous system on hepatic glucose production. Increased expression of liver Adra1b in obese models suggests that it could contribute to the hyperglycemic state. We believe that a better understanding of the receptors and pathways involved in the sympathetic outflow will help developing a thoughtful perspective on how the autonomic control of peripheral organs is altered in metabolic diseases.