Mitochondrial dysfunction and activation of iNOS are responsible for the palmitate-induced decrease in adiponectin synthesis in 3T3L1 adipocytes.
Mitochondrial dysfunction and endoplasmic reticulum (ER) stress are considered the key determinants of insulin resistance. Impaired mitochondrial function in obese animals was shown to induce the ER stress response, resulting in reduced adiponectin synthesis in adipocytes. The expression of inducible nitric oxide synthase (iNOS) is increased in adipose tissues in genetic and dietary models of obesity. In this study, we examined whether activation of iNOS is responsible for palmitate-induced mitochondrial dysfunction, ER stress, and decreased adiponectin synthesis in 3T3L1 adipocytes. As expected, palmitate increased the expression levels of iNOS and ER stress response markers, and decreased mitochondrial contents. Treatment with iNOS inhibitor increased adiponectin synthesis and reversed the palmitate-induced ER stress response. However, the iNOS inhibitor did not affect the palmitate-induced decrease in mitochondrial contents. Chemicals that inhibit mitochondrial function increased iNOS expression and the ER stress response, whereas measures that increase mitochondrial biogenesis (rosiglitazone and adenoviral overexpression of nuclear respiratory factor-1) reversed them. Inhibition of mitochondrial biogenesis prevented the rosiglitazone-induced decrease in iNOS expression and increase in adiponectin synthesis. These results suggest that palmitate-induced mitochondrial dysfunction is the primary event that leads to iNOS induction, ER stress, and decreased adiponectin synthesis in cultured adipocytes.
Asan Institute for Life Sciences, Seoul 138-736, Korea.
Min Jae
MJ
Jeon
Jaechan
J
Leem
Myoung Seok
MS
Ko
Jung Eun
JE
Jang
Hye-Sun
HS
Park
Hyun Sik
HS
Kim
Mina
M
Kim
Eun Hee
EH
Kim
Hyun Ju
HJ
Yoo
Chul-Ho
CH
Lee
In-Sun
IS
Park
Ki-Up
KU
Lee
Eun Hee
EH
Koh
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D052242:Adiponectin / Q000096:biosynthesis; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D007333:Insulin Resistance / Q000235:genetics; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D063269:Mitochondrial Turnover / Q000187:drug effects / Q000235:genetics; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D051266:Nuclear Respiratory Factor 1; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D019308:Palmitic Acid / Q000494:pharmacology; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology
D052242:Adiponectin; C495634:Nrf1 protein, mouse; D051266:Nuclear Respiratory Factor 1; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D019308:Palmitic Acid; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse