Reduced adipocyte glutaminase activity promotes energy expenditure and metabolic health

被引：14

作者：

Lecoutre, Simon ^{[1
,2
]}

Maqdasy, Salwan ^{[1
]}

Rizo-Roca, David ^{[3
]}

Renzi, Gianluca ^{[1
]}

Vlassakev, Ivan ^{[1
]}

Alaeddine, Lynn M. ^{[1
]}

Higos, Romane ^{[1
]}

Jalkanen, Jutta ^{[1
]}

Zhong, Jiawei ^{[1
]}

Zareifi, Danae S. ^{[1
]}

Frendo-Cumbo, Scott ^{[1
]}

Massier, Lucas ^{[1
]}

Hodek, Ondrej ^{[4
]}

Juvany, Marta ^{[4
]}

Moritz, Thomas ^{[4
,5
]}

de Castro Barbosa, Thais ^{[1
]}

Omar-Hmeadi, Muhmmad ^{[1
]}

Lopez-Yus, Marta ^{[6
,7
,8
]}

Merabtene, Fatiha ^{[2
]}

Abatan, Jimon Boniface ^{[2
]}

Marcelin, Genevieve ^{[2
]}

El Hachem, Elie-Julien ^{[2
]}

Rouault, Christine ^{[2
]}

Bergo, Martin O. ^{[9
]}

Petrus, Paul ^{[1
]}

Zierath, Juleen R. ^{[3
,10
]}

Clement, Karine ^{[2
,11
]}

Krook, Anna ^{[3
]}

Mejhert, Niklas ^{[1
]}

Ryden, Mikael ^{[1
]}

机构：

[1] Karolinska Univ Hosp Huddinge, Karolinska Inst, Dept Med Huddinge, ME Endokrinol, Huddinge, Sweden

[2] Sorbonne Univ, Nutr & Obes Syst Approaches Res Grp, NutriOm, INSERM, Paris, France

[3] Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden

[4] Swedish Univ Agr Sci, Swedish Metabol Ctr, Dept Forest Genet & Plant Physiol, Umea, Sweden

[5] Univ Copenhagen, Novo Nord Fdn Ctr Basic Metab Res, Fac Hlth & Med Sci, Copenhagen, Denmark

[6] Univ Hosp Miguel Servet, Translat Res Unit, Adipocyte & Fat Biol Lab AdipoFat, Zaragoza, Spain

[7] Inst Aragones Ciencias Salud IACS, Zaragoza, Spain

[8] Inst Invest Sanitaria Aragon IIS Aragon, Zaragoza, Spain

[9] Karolinska Inst, Dept Biosci & Nutr, Huddinge, Sweden

[10] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden

[11] Hop La Pitie Salpetriere, AP HP, Nutr Dept, CRNH Ile de France, Paris, France

来源：

NATURE METABOLISM | 2024年 / 6卷 / 07期

基金：

瑞典研究理事会;

关键词：

ACTIVATED PROTEIN-KINASE; INSULIN-RESISTANCE; BRANCHED-CHAIN; MAP KINASE; FAT-CELLS; ADIPOSE; LACTATE; EXTRACTION; GLUTAMATE; LIPOLYSIS;

D O I：

10.1038/s42255-024-01083-y

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Glutamine and glutamate are interconverted by several enzymes and alterations in this metabolic cycle are linked to cardiometabolic traits. Herein, we show that obesity-associated insulin resistance is characterized by decreased plasma and white adipose tissue glutamine-to-glutamate ratios. We couple these stoichiometric changes to perturbed fat cell glutaminase and glutamine synthase messenger RNA and protein abundance, which together promote glutaminolysis. In human white adipocytes, reductions in glutaminase activity promote aerobic glycolysis and mitochondrial oxidative capacity via increases in hypoxia-inducible factor 1 alpha abundance, lactate levels and p38 mitogen-activated protein kinase signalling. Systemic glutaminase inhibition in male and female mice, or genetically in adipocytes of male mice, triggers the activation of thermogenic gene programs in inguinal adipocytes. Consequently, the knockout mice display higher energy expenditure and improved glucose tolerance compared to control littermates, even under high-fat diet conditions. Altogether, our findings highlight white adipocyte glutamine turnover as an important determinant of energy expenditure and metabolic health. Lecoutre, Maqdasy and Rizo-Roca show that whole-body pharmacological inhibition or adipocyte-specific deletion of glutaminase in mice activates thermogenesis in inguinal adipocytes and promotes metabolic health. They also link decreased plasma and adipose tissue glutamine-to-glutamate ratios to insulin resistance in humans with obesity.

引用

页码：1329 / 1346

页数：31