Mediobasal hypothalamic PTEN modulates hepatic insulin resistance independently of food intake in rats

Takashi Sumita, Hiraku Ono, Tokuko Suzuki, Gota Sakai, Kouichi Inukai, Hideki Katagiri, Tomoichiro Asano, Shigehiro Katayama, Takuya Awata

研究成果: Article査読

10 被引用数 (Scopus)

抄録

Phosphatase and tensin homolog (PTEN) dephosphorylates phosphatidylinositol (PI) 3,4,5-triphosphate and antagonizes PI 3-kinase. Insulin acts in the mediobasal hypothalamus (MBH) to not only suppress food intake and weight gain but also improve glucose metabolism via PI 3-kinase activation. Thus, the blocking of hypothalamic PTEN is a potential target for treating obesity as well as diabetes. However, genetic modification of PTEN in specific neuronal populations in the MBH yielded complex results, and no postnatal intervention for hypothalamic PTEN has been reported yet. To elucidate how postnatal modification of hypothalamic PTEN influences food intake as well as glucose metabolism, we bidirectionally altered PTEN activity in the MBH of rats by adenoviral gene delivery. Inhibition of MBH PTEN activity reduced food intake and weight gain, whereas constitutive activation of PTEN tended to induce the opposite effects. Interestingly, the effects of MBH PTEN intervention on food intake and body weight were blunted by high-fat feeding. However, MBH PTEN blockade improved hepatic insulin sensitivity even under high-fat-fed conditions. On the other hand, constitutive activation of MBH PTEN induced hepatic insulin resistance. Hepatic Akt phosphorylation and the G6Pase expression level were modulated bidirectionally by MBH PTEN intervention. These results demonstrate that PTEN in the MBH regulates hepatic insulin sensitivity independently of the effects on food intake and weight gain. Therefore, hypothalamic PTEN is a promising target for treating insulin resistance even in states of overnutrition.

本文言語English
ページ(範囲)E47-E60
ジャーナルAmerican Journal of Physiology - Endocrinology and Metabolism
307
1
DOI
出版ステータスPublished - 2014 7 1
外部発表はい

ASJC Scopus subject areas

  • 内分泌学、糖尿病および代謝内科学
  • 生理学
  • 生理学(医学)

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