Deletion of Lkb1 in Pro-Opiomelanocortin Neurons Impairs Peripheral Glucose Homeostasis in Mice

被引：47

作者：

Claret, Marc ^{[1
]}

Smith, Mark A. ^{[2
,3
]}

Knauf, Claude ^{[4
]}

Al-Qassab, Hind ^{[2
]}

Woods, Angela ^{[5
]}

Heslegrave, Amanda ^{[5
]}

Piipari, Kaisa ^{[2
]}

Emmanuel, Julian J. ^{[6
]}

Colom, Andre ^{[4
]}

Valet, Philippe ^{[4
]}

Cani, Patrice D. ^{[7
]}

Begum, Ghazala ^{[8
,9
]}

White, Anne ^{[8
,9
]}

Mucket, Phillip ^{[5
]}

Peters, Marco ^{[10
]}

Mizuno, Keiko ^{[10
]}

Batterham, Rachel L. ^{[6
]}

Giese, K. Peter ^{[10
]}

Ashworth, Alan ^{[11
]}

Burcelin, Remy ^{[4
]}

Ashford, Michael L. ^{[3
]}

Carling, David ^{[5
]}

Withers, Dominic J. ^{[2
]}

机构：

[1] Hosp Clin Barcelona, Inst Invest Biomed August Pi & Sunyer, Lab Diabet & Obes, Endocrinol & Nutr Unit, Barcelona, Spain

[2] Univ London Imperial Coll Sci Technol & Med, Ctr Clin Sci, MRC, Metab Signalling Grp, London, England

[3] Univ Dundee, Ninewells Hosp & Med Sch, Biomed Res Ctr, Dundee DD1 9SY, Scotland

[4] Inst Natl Sante & Rech Med U858, Inst Med Mol Rangueil, Toulouse, France

[5] Univ London Imperial Coll Sci Technol & Med, Ctr Clin Sci, MRC, Cellular Stress Grp, London, England

[6] UCL, Ctr Diabet & Endocrinol, Rayne Inst, London, England

[7] Catholic Univ Louvain, Louvain Drug Res Inst, Unit Pharmacokinet Metab Nutr & Toxicol, B-1200 Brussels, Belgium

[8] Univ Manchester, Fac Life Sci, Manchester, Lancs, England

[9] Univ Manchester, Manchester Acad Hlth Sci Ctr, Fac Med & Human Sci, Manchester, Lancs, England

[10] Kings Coll London, Ctr Cellular Basis Behav, Inst Psychiat, London WC2R 2LS, England

[11] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England

来源：

DIABETES | 2011年 / 60卷 / 03期

基金：

英国生物技术与生命科学研究理事会; 英国惠康基金; 英国医学研究理事会;

关键词：

ACTIVATED PROTEIN-KINASE; INCREASES INSULIN SENSITIVITY; HEPATIC GLUCOSE; MELANOCORTIN PATHWAYS; RECEPTOR SUBSTRATE-2; UPSTREAM KINASE; ARCUATE NUCLEUS; AGRP NEURONS; SAD KINASES; FOOD-INTAKE;

D O I：

10.2337/db10-1055

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

OBJECTIVE AMP-activated protein kinase (AMPK) signaling acts as a sensor of nutrients and hormones in the hypothalamus, thereby regulating whole-body energy homeostasis. Deletion of Ampk alpha 2 in pro-opiomelanocortin (POMC) neurons causes obesity and defective neuronal glucose sensing. LKB1, the Peutz-Jeghers syndrome gene product, and Ca2+-calmodulin-dependent protein kinase kinase beta (CaMKK beta) are key upstream activators of AMPK. This study aimed to determine their role in POMC neurons upon energy and glucose homeostasis regulation. RESEARCH DESIGN AND METHODS Mice lacking either Camkk beta or Lkb1 in POMC neurons were generated, and physiological, electrophysiological, and molecular biology studies were performed. RESULTS Deletion of Camkk beta in POMC neurons does not alter energy homeostasis or glucose metabolism. In contrast, female mice lacking Lkb1 in POMC neurons (PomcLkb1KO) display glucose intolerance, insulin resistance, impaired suppression of hepatic glucose production, and altered expression of hepatic metabolic genes. The underlying cellular defect in PomcLkb1KO mice involves a reduction in melanocortin tone caused by decreased alpha-melanocyte-stimulating hormone secretion. However, Lkb1-deficient POMC neurons showed normal glucose sensing, and body weight was unchanged in PomcLkb1KO mice. CONCLUSIONS Our findings demonstrate that LKB1 in hypothalamic POMC neurons plays a key role in the central regulation of peripheral glucose metabolism but not body-weight control. This phenotype contrasts with that seen in mice lacking AMPK in POMC neurons with defects in body-weight regulation but not glucose homeostasis, which suggests that LKB1 plays additional functions distinct from activating AMPK in POMC neurons. Diabetes 60:735-745, 2011

引用

页码：735 / 745

页数：11