Journal
DIABETES
Volume 59, Issue 10, Pages 2435-2443Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db10-0221
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Funding
- Canadian Institute of Health Research [MOP-86554]
- Canadian Institute of Health Research (CIHR)
- Ontario Graduate Scholarship
- Banting and Best Diabetes Centre at the University of Toronto (BBDC)
- BBDC
- Wellcome Trust [081958/7/07/Z, WT082366MA]
- Medical Research Council [G0401641]
- National Institutes of Health [ROT DKO71962-01]
- European Union
- Diabetes U.K [BDA:RD04/0002895]
- MRC [G0401641] Funding Source: UKRI
- Medical Research Council [G0401641] Funding Source: researchfish
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OBJECTIVE The fuel sensor AMP-activated protein kinase (AMPK) in the hypothalamus regulates energy homeostasis by sensing nutritional and hormonal signals. However, the role of hypothalamic AMPK in glucose production regulation remains to be elucidated. We hypothesize that bidirectional changes in hypothalamic AMPK activity alter glucose production. RESEARCH DESIGN AND METHODS To introduce bidirectional changes in hypothalamic AMPK activity in vivo, we first knocked down hypothalamic AMPK activity in male Sprague-Dawley rats by either injecting an adenovirus expressing the dominant-negative form of AMPK (Ad-DN AMPK alpha 2 [D(157)A]) or infusing AMPK inhibitor compound C directly into the mediobasal hypothalamus. Next, we independently activated hypothalamic AMPK by delivering either an adenovirus expressing the constitutive active form of AMPK (Ad-CA AMPK alpha 1(312) [T172D]) or the AMPK activator AICAR. The pancreatic (basal insulin)euglycemic clamp technique in combination with the tracerdilution methodology was used to assess the impact of alternations in hypothalamic AMPK activity on changes in glucose kinetics in vivo. RESULTS Injection of Ad-DN AMPK into the hypothalamus knocked down hypothalamic AMPK activity and led to a significant suppression of glucose production with no changes in peripheral glucose uptake during the clamps. In parallel, hypothalamic infusion of AMPK inhibitor compound C lowered glucose production as well. Conversely, molecular and pharmacological activation of hypothalamic AMPK negated the ability of hypothalamic nutrients to lower glucose production. CONCLUSIONS These data indicate that changes in hypothalamic AMPK activity are sufficient and necessary for hypothalamic nutrient-sensing mechanisms to alter glucose production in vivo. Diabetes 59:2435-2443, 2010
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