Caloric restriction decreases ER stress in liver and adipose tissue in ob/ob mice.
Endoplasmic reticulum (ER) stress plays a crucial role in the development of insulin resistance and diabetes. Although caloric restriction (CR) improves obesity-related disorders, the effects of CR on ER stress in obesity remain unknown. To investigate how CR affects ER stress in obesity, ob/ob mice were assigned to either ad libitum (AL) (ob-AL) or CR (ob-CR) feeding (2 g food/day) for 1-4 weeks. The body weight (BW) of ob-CR mice decreased to the level of lean AL-fed littermates (lean-AL) within 2 weeks. BW of lean-AL and ob-CR mice was less than that of ob-AL mice. The ob-CR mice showed improved glucose tolerance and hepatic insulin action compared with ob-AL mice. Levels of ER stress markers such as phosphorylated PKR-like ER kinase (PERK) and eukaryotic translation initiation factor 2α and the mRNA expression of activating transcription factor 4 were significantly higher in the liver and epididymal fat from ob-AL mice compared with lean-AL mice. CR for 2 and 4 weeks significantly reduced all of these markers to less than 35% and 50%, respectively, of the levels in ob-AL mice. CR also significantly reduced the phosphorylation of insulin receptor substrate (IRS)-1 and c-Jun NH(2)-terminal kinase (JNK) in ob/ob mice. The CR-mediated decrease in PERK phosphorylation was similar to that induced by 4-phenyl butyric acid, which reduces ER stress in vivo. In conclusion, CR reduced ER stress and improved hepatic insulin action by suppressing JNK-mediated IRS-1 serine-phosphorylation in ob/ob mice.
Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
Atsuyuki
A
Tsutsumi
Hiroyuki
H
Motoshima
Tatsuya
T
Kondo
Shuji
S
Kawasaki
Takeshi
T
Matsumura
Satoko
S
Hanatani
Motoyuki
M
Igata
Norio
N
Ishii
Hiroyuki
H
Kinoshita
Junji
J
Kawashima
Kayo
K
Taketa
Noboru
N
Furukawa
Kaku
K
Tsuruzoe
Takeshi
T
Nishikawa
Eiichi
E
Araki
D000273:Adipose Tissue / Q000502:physiology*; D000818:Animals; D001835:Body Weight; D031204:Caloric Restriction; D004721:Endoplasmic Reticulum / Q000502:physiology*; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology / Q000502:physiology; D008099:Liver / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D009765:Obesity / Q000503:physiopathology*; D013312:Stress, Physiological
D007328:Insulin; D005947:Glucose