Failure of the feeding response to fasting in carnitine-deficient juvenile visceral steatosis (JVS) mice: Involvement of defective acyl-ghrelin secretion and enhanced corticotropin-releasing factor signaling in the hypothalamus

Takeo Sakoguchi (1) , Masahisa Horiuchi (2) , Akihiro Asakawa (1) , Miharu Ushikai (1) , Goichiro Yoshida (3, 4) , Mineko Fujimiya (5) , Ikuo Kato (6) , Masamitsu Nakazato (7) , Toru Takeuchi (2) , Takeyori Saheki (3, 8) , Akio Inui (1)

1 Department of Psychosomatic Internal Medicine
2 Department of Environmental Medicine
3 Department of Molecular Metabolism and Biochemical Genetics
4 Department of Health Science
5 Department of Anatomy
6 Hokuriku University
7 Third Department of Internal Medicine
8 Tokushima Bunri University

Carnitine-deficient juvenile visceral steatosis (JVS) mice, suffering from fatty acid metabolism abnormalities, have reduced locomotor activity after fasting. We examined whether JVS mice exhibit specific defect in the feeding response to fasting, a key process of anti-famine homeostatic mechanism. Carnitine-deficient JVS mice showed grossly defective feeding response to 24h-fasting, with almost no food intake in the first 4 h, in marked contrast to control animals. JVS mice also showed defective acyl-ghrelin response to fasting, less suppressed leptin, and seemingly normal corticotropin-releasing factor (CRF) expression in the hypothalamus despite markedly increased plasma corticosterone. The anorectic response was ameliorated by intraperitoneal administration of carnitine or acyl-ghrelin, with decreased CRF expression. Intracerebroventricular treatment of CRF type 2 receptor antagonist, antisauvagine-30, recovered the defective feeding response of 24h-fasted JVS mice. The defective feeding response to fasting in carnitine-deficient JVS mice is due to the defective acyl-ghrelin and enhanced CRF signaling in the hypothalamus through fatty acid metabolism abnormalities. In this animal model, carnitine normalizes the feeding response through an inhibition of CRF.

Mots clés: aCSF; ACTH; AGRP; CART; CRF; FAO; icv; ip; JVS; NPY; OCTN2; POMC; anti-famine homeostatic mechanism; fatty acid metabolism abnormalities; ghrelin; hypothalamus-pituitary-adrenal axis

Takeo Sakoguchi, Masahisa Horiuchi, Akihiro Asakawa, Miharu Ushikai, Goichiro Yoshida, et al.. Failure of the feeding response to fasting in carnitine-deficient juvenile visceral steatosis (JVS) mice: Involvement of defective acyl-ghrelin secretion and enhanced corticotropin-releasing factor signaling in the hypothalamus. Biochimica et Biophysica Acta - Molecular Basis of Disease, 2009, 1792 (11), pp.1087. ⟨10.1016/j.bbadis.2009.09.001⟩. ⟨hal-00562932⟩