Brain-derived neurotropic factor (BDNF) mediates many aspects of neuronal function, and plays a chief role in the central regulation of energy balance. In the periphery, it is expressed in organs involved in energy, lipid, and glucose homeostasis, including the liver, but its role there remains unclear. Here, we describe studies examining the effect of selectively depleting hepatic BDNF. Liver-specific mutant mice exhibited normal food intake and body weights when fed standard chow or high-fat diets (HFDs). However, whereas HFD intake induced mild hyperglycemia and hyperinsulinemia in wild-types (WTs), liver-specific BDNF mutants were protected from these effects. Serum levels of cholesterol and triglycerides were also elevated in HFD-fed WTs, but they were normal or slightly increased in BDNF mutants. Furthermore, whereas WTs fed HFD exhibited elevated levels of circulating alanine aminotransferase and aspartate aminotransferase, BDNF mutant males fed a similar diet had a normal content of both enzymes. Molecular analysis indicated that the livers of BDNF mutants fed HFD contained elevated levels of peroxisome proliferator-activated receptor alpha (Pparalpha or Ppara as listed in the MGI Database) and fibroblast growth factor 21 (Fgf21) transcripts compared with WTs. This is a notable finding as this pathway has anti-diabetic and lipid clearance effects. Accordingly, genes involved in lipid and glucose handling and targets of PPARalpha and FGF21 were upregulated in the BDNF mutant livers. The collective data indicate that hepatic BDNF might facilitate the emergence of insulin resistance, dyslipidemia, and liver disease following HFD challenge by suppressing PPARalpha and FGF21.