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FEBS Open Bio. 2013 Sep 11;3:443-9. doi: 10.1016/j.fob.2013.09.002. eCollection 2013.

Diet-induced obesity induces endoplasmic reticulum stress and insulin resistance in the amygdala of rats.

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School of Applied Sciences, State University of Campinas (UNICAMP), Campinas, SP, Brazil.


Insulin acts in the hypothalamus, decreasing food intake (FI) by the IR/PI3K/Akt pathway. This pathway is impaired in obese animals and endoplasmic reticulum (ER) stress and low-grade inflammation are possible mechanisms involved in this impairment. Here, we highlighted the amygdala as an important brain region for FI regulation in response to insulin. This regulation was dependent on PI3K/AKT pathway similar to the hypothalamus. Insulin was able to decrease neuropeptide Y (NPY) and increase oxytocin mRNA levels in the amygdala via PI3K, which may contribute to hypophagia. Additionally, obese rats did not reduce FI in response to insulin and AKT phosphorylation was decreased in the amygdala, suggesting insulin resistance. Insulin resistance was associated with ER stress and low-grade inflammation in this brain region. The inhibition of ER stress with PBA reverses insulin action/signaling, decreases NPY and increases oxytocin mRNA levels in the amygdala from obese rats, suggesting that ER stress is probably one of the mechanisms that induce insulin resistance in the amygdala.


AGRP, agouti-related peptide; AMY, amygdala; Amygdala; BW, body weight; CNS, central nervous system; CRH, corticotrophin-releasing hormone; ER, endoplasmic reticulum; Endoplasmic reticulum stress; FI, food intake; FKBP51, FK506 binding protein 51; HFD, high-fat diet; HPRT, hypoxanthine phosphoribosyl transferase; IKKβ, I kappa B kinase; IR, insulin receptor; IRE1α, inositol-requiring kinase alpha; IRS-1, insulin substrate 1; Inflammation; Insulin; JNK, c-Jun N-terminal kinase; LGI, low-grade inflammation; NPY; NPY, neuropeptide Y; Obesity; Oxytocin; PBA, 4-phenyl butyric acid; PERK, RNA-activated protein kinase-like ER resident kinase; PI3K, phosphoinositide 3-kinase; PKB or Akt, protein kinase B; Phosphatidylinositol 3-kinase

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