Pharmacological Inhibition of PI3K Reduces Adiposity and Metabolic Syndrome in Obese Mice and Rhesus Monkeys

被引：85

作者：

Ortega-Molina, Ana ^{[1
]}

Lopez-Guadamillas, Elena ^{[1
]}

Mattison, Julie A. ^{[2
]}

Mitchell, Sarah J. ^{[2
]}

Munoz-Martin, Maribel ^{[1
]}

Iglesias, Gema ^{[1
]}

Gutierrez, Vincent M. ^{[2
]}

Vaughan, Kelli L. ^{[2
,3
]}

Szarowicz, Mark D. ^{[2
,3
]}

Gonzalez-Garcia, Ismael ^{[4
]}

Lopez, Miguel ^{[4
]}

Cebrian, David ^{[5
]}

Martinez, Sonia ^{[5
]}

Pastor, Joaquin ^{[5
]}

de Cabo, Rafael ^{[2
]}

Serrano, Manuel ^{[1
]}

机构：

[1] Spanish Natl Canc Res Ctr CNIO, Tumor Suppress Grp, Madrid 28029, Spain

[2] NIA, Translat Gerontol Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA

[3] SoBran Inc, Burtonsville, MD 20866 USA

[4] Univ Santiago de Compostela, CIBER Fisiopatol Obesidad & Nutr CIBERobn, Inst Invest Sanitaria, Dept Physiol,CIMUS, Santiago De Compostela 15782, Spain

[5] Spanish Natl Canc Res Ctr CNIO, Expt Therapeut Programme, Madrid 28029, Spain

来源：

CELL METABOLISM | 2015年 / 21卷 / 04期

基金：

欧洲研究理事会;

关键词：

CALORIC RESTRICTION; ENERGY-EXPENDITURE; THERMOGENESIS; PI3K-GAMMA; PATHWAY;

D O I：

10.1016/j.cmet.2015.02.017

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Genetic inhibition of PI3K signaling increases energy expenditure, protects from obesity and metabolic syndrome, and extends longevity. Here, we show that two pharmacological inhibitors of PI3K, CNIO-PI3Ki and GDC-0941, decrease the adiposity of obese mice without affecting their lean mass. Longterm treatment of obese mice with low doses of CNIO-PI3Ki reduces body weight until reaching a balance that is stable for months as long as the treatment continues. CNIO-PI3Ki treatment also ameliorates liver steatosis and decreases glucose serum levels. The above observations have been recapitulated in independent laboratories and using different oral formulations of CNIO-PI3Ki. Finally, daily oral treatment of obese rhesus monkeys for 3 months with low doses of CNIO-PI3Ki decreased their adiposity and lowered their serum glucose levels, in the absence of detectable toxicities. Therefore, pharmacological inhibition of PI3K is an effective and safe anti-obesity intervention that could reverse the negative effects of metabolic syndrome in humans.

引用

页码：558 / 570

页数：13

共 30 条

[1] The Critical Role of Metabolic Pathways in Aging [J].

Barzilai, Nir ;

Huffman, Derek M. ;

Muzumdar, Radhika H. ;

Bartke, Andrzej .

DIABETES, 2012, 61 (06) :1315-1322

[2] PI3Kγ within a nonhematopoietic cell type negatively regulates diet-induced thermogenesis and promotes obesity and insulin resistance [J].

Becattini, Barbara ;

Marone, Romina ;

Zani, Fabio ;

Arsenijevic, Denis ;

Seydoux, Josiane ;

Montani, Jean-Pierre ;

Dulloo, Abdul G. ;

Thorens, Bernard ;

Preitner, Frederic ;

Wymann, Matthias P. ;

Solinas, Giovanni .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2011, 108 (42) :E854-E863

[3] Will calorie restriction work in humans? [J].

Cava, Edda ;

Fontana, Luigi .

AGING-US, 2013, 5 (07) :507-514

[4] Ablation of PI3K p110-α Prevents High-Fat Diet-Induced Liver Steatosis [J].

Chattopadhyay, Mohar ;

Selinger, Elzbieta S. ;

Ballou, Lisa M. ;

Lin, Richard Z. .

DIABETES, 2011, 60 (05) :1483-1492

[5] Caloric Restriction Delays Disease Onset and Mortality in Rhesus Monkeys [J].

Colman, Ricki J. ;

Anderson, Rozalyn M. ;

Johnson, Sterling C. ;

Kastman, Erik K. ;

Kosmatka, Kristopher J. ;

Beasley, T. Mark ;

Allison, David B. ;

Cruzen, Christina ;

Simmons, Heather A. ;

Kemnitz, Joseph W. ;

Weindruch, Richard .

SCIENCE, 2009, 325 (5937) :201-204

[6] The arcuate nucleus as a conduit for diverse signals relevant to energy homeostasis [J].

Cone, RD ;

Cowley, MA ;

Butler, AA ;

Fan, W ;

Marks, DL ;

Low, MJ .

INTERNATIONAL JOURNAL OF OBESITY, 2001, 25 (Suppl 5) :S63-S67

[7] Extending Healthy Life Span-From Yeast to Humans [J].

Fontana, Luigi ;

Partridge, Linda ;

Longo, Valter D. .

SCIENCE, 2010, 328 (5976) :321-326

[8] Long-term p110 PI3K inactivation exerts a beneficial effect on metabolism [J].

Foukas, Lazaros C. ;

Bilanges, Benoit ;

Bettedi, Lucia ;

Pearce, Wayne ;

Ali, Khaled ;

Sancho, Sara ;

Withers, Dominic J. ;

Vanhaesebroeck, Bart .

EMBO MOLECULAR MEDICINE, 2013, 5 (04) :563-571

[9] Systemic Elevation of PTEN Induces a Tumor-Suppressive Metabolic State [J].

Garcia-Cao, Isabel ;

Song, Min Sup ;

Hobbs, Robin M. ;

Laurent, Gaelle ;

Giorgi, Carlotta ;

de Boer, Vincent C. J. ;

Anastasiou, Dimitrios ;

Ito, Keisuke ;

Sasaki, Atsuo T. ;

Rameh, Lucia ;

Carracedo, Arkaitz ;

Vander Heiden, Matthew G. ;

Cantley, Lewis C. ;

Pinton, Paolo ;

Haigis, Marcia C. ;

Pandolfi, Pier Paolo .

CELL, 2012, 149 (01) :49-62

[10] Glucose homeostasis and tissue transcript content of insulin signaling intermediates in four inbred strains of mice: C57BL/6, C57BLKS/6, DBA/2, and 129X1 [J].

Goren, HJ ;

Kulkarni, RN ;

Kahn, CR .

ENDOCRINOLOGY, 2004, 145 (07) :3307-3323

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