Obesity arises from impaired energy balance, which is centrally coordinated by
leptin through activation of the long form of
leptin receptor (Leprb).
Obesity causes central
leptin resistance. However, whether enhanced peripheral
leptin sensitivity could overcome central
leptin resistance remains obscure. A peripheral metabolic organ targeted by
leptin is the liver, with low Leprb expression. We here show that mice fed a high-fat diet (HFD) and obese patients with hepatosteatosis exhibit increased expression of hepatic helicase with zinc finger 2, a transcriptional coactivator (Helz2), which functions as a transcriptional coregulator of several
nuclear receptors, including
peroxisome proliferator-activated receptor γ in vitro. To explore the physiological importance of Helz2, we generated Helz2-deficient mice and analyzed their metabolic phenotypes. Helz2-deficient mice showing hyperleptinemia associated with central
leptin resistance were protected against HFD-induced
obesity and had significantly up-regulated hepatic Leprb expression. Helz2 deficiency and adenovirus-mediated liver-specific exogenous Leprb overexpression in wild-type mice significantly stimulated hepatic
AMP-activated protein kinase on HFD, whereas Helz2-deficient db/db mice lacking functional Leprb did not.
Fatty acid-β oxidation was increased in Helz2-deficeint hepatocytes, and Helz2-deficient mice revealed increased oxygen consumption and decreased respiratory quotient in calorimetry analyses. The enhanced hepatic
AMP-activated protein kinase energy-sensing pathway in Helz2-deficient mice ameliorated
hyperlipidemia, hepatosteatosis, and
insulin resistance by reducing lipogenic gene expression and stimulating
lipid-burning gene expression in the liver. These findings together demonstrate that Helz2 deficiency ameliorates HFD-induced metabolic abnormalities by stimulating endogenous hepatic Leprb expression, despite central
leptin resistance. Hepatic HELZ2 might be a novel target molecule for the treatment of
obesity with hepatosteatosis.