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Am J Physiol Endocrinol Metab. 2014 Jul 1;307(1):E47-60. doi: 10.1152/ajpendo.00361.2013. Epub 2014 May 13.

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

Author information

  • 1Department of Endocrinology and Diabetes, School of Medicine, Saitama Medical University, Moroyama, Saitama, Japan;
  • 2Department of Endocrinology and Diabetes, School of Medicine, Saitama Medical University, Moroyama, Saitama, Japan; hono@saitama-med.ac.jp.
  • 3Department of Metabolic Diseases, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan; and.
  • 4Department of Medical Science, Graduate School of Medicine, University of Hiroshima, Hiroshima, Japan.

Abstract

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.

Copyright © 2014 the American Physiological Society.

KEYWORDS:

hypothalamus; insulin resistance; liver; phosphatase and tensin homolog

PMID:
24824654
[PubMed - indexed for MEDLINE]
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