title: Protection against high-fat diet-induced obesity in Helz2-deficient male mice due to enhanced expression of hepatic leptin receptor.
abstract: 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.
authors.affiliation: Departments of Medicine and Molecular Science (S.Y., T.Sat., M.Y., K.H., T.To., A.K.-T., S.K., S.O., H.S., A.O., T.Tu., Ma.Mori) and Human Pathology (H.I., Y.N.), Gunma University Graduate School of Medicine, Maebashi, 371-8511 Japan; Laboratory of Biosignal Sciences (Mu.Mori, T.Ma.) and Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation (T.Sas., T.K.), Gunma University, Maebashi, 371-8512 Japan; and Kitakanto Molecular Novel Research Institute for Obesity and Metabolism (Ma.Mori), Midori, 379-2311 Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yoshino
authors.forename: Tetsurou
authors.initials: T
authors.lastname: Satoh
authors.forename: Masanobu
authors.initials: M
authors.lastname: Yamada
authors.forename: Koshi
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Takuya
authors.initials: T
authors.lastname: Tomaru
authors.forename: Akiko
authors.initials: A
authors.lastname: Katano-Toki
authors.forename: Satoru
authors.initials: S
authors.lastname: Kakizaki
authors.forename: Shuichi
authors.initials: S
authors.lastname: Okada
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shimizu
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ozawa
authors.forename: Takafumi
authors.initials: T
authors.lastname: Tuchiya
authors.forename: Hayato
authors.initials: H
authors.lastname: Ikota
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Nakazato
authors.forename: Munemasa
authors.initials: M
authors.lastname: Mori
authors.forename: Takashi
authors.initials: T
authors.lastname: Matozaki
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Sasaki
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Kitamura
authors.forename: Masatomo
authors.initials: M
authors.lastname: Mori
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects*; D005234:Fatty Liver / Q000201:enzymology; D005260:Female; D006801:Humans; D007328:Insulin / Q000378:metabolism; D020738:Leptin / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D020365:RNA Helicases / Q000172:deficiency* / Q000235:genetics; D054411:Receptors, Leptin / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D007328:Insulin; D020738:Leptin; D054411:Receptors, Leptin; D055372:AMP-Activated Protein Kinases; C562220:HELZ protein, mouse; D020365:RNA Helicases