title: Partial inhibition of adipose tissue lipolysis improves glucose metabolism and insulin sensitivity without alteration of fat mass.
abstract: When energy is needed, white adipose tissue (WAT) provides fatty acids (FAs) for use in peripheral tissues via stimulation of fat cell lipolysis. FAs have been postulated to play a critical role in the development of obesity-induced insulin resistance, a major risk factor for diabetes and cardiovascular disease. However, whether and how chronic inhibition of fat mobilization from WAT modulates insulin sensitivity remains elusive. Hormone-sensitive lipase (HSL) participates in the breakdown of WAT triacylglycerol into FAs. HSL haploinsufficiency and treatment with a HSL inhibitor resulted in improvement of insulin tolerance without impact on body weight, fat mass, and WAT inflammation in high-fat-diet-fed mice. In vivo palmitate turnover analysis revealed that blunted lipolytic capacity is associated with diminution in FA uptake and storage in peripheral tissues of obese HSL haploinsufficient mice. The reduction in FA turnover was accompanied by an improvement of glucose metabolism with a shift in respiratory quotient, increase of glucose uptake in WAT and skeletal muscle, and enhancement of de novo lipogenesis and insulin signalling in liver. In human adipocytes, HSL gene silencing led to improved insulin-stimulated glucose uptake, resulting in increased de novo lipogenesis and activation of cognate gene expression. In clinical studies, WAT lipolytic rate was positively and negatively correlated with indexes of insulin resistance and WAT de novo lipogenesis gene expression, respectively. In obese individuals, chronic inhibition of lipolysis resulted in induction of WAT de novo lipogenesis gene expression. Thus, reduction in WAT lipolysis reshapes FA fluxes without increase of fat mass and improves glucose metabolism through cell-autonomous induction of fat cell de novo lipogenesis, which contributes to improved insulin sensitivity.
authors: INSERM, UMR1048, Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France ; University of Toulouse, UMR1048, Paul Sabatier University, France.
authors: Amandine
authors: A
authors: Girousse
authors: Geneviève
authors: G
authors: Tavernier
authors: Carine
authors: C
authors: Valle
authors: Cedric
authors: C
authors: Moro
authors: Niklas
authors: N
authors: Mejhert
authors: Anne-Laure
authors: AL
authors: Dinel
authors: Marianne
authors: M
authors: Houssier
authors: Balbine
authors: B
authors: Roussel
authors: Aurèle
authors: A
authors: Besse-Patin
authors: Marion
authors: M
authors: Combes
authors: Lucile
authors: L
authors: Mir
authors: Laurent
authors: L
authors: Monbrun
authors: Véronic
authors: V
authors: Bézaire
authors: Bénédicte
authors: B
authors: Prunet-Marcassus
authors: Aurélie
authors: A
authors: Waget
authors: Isabelle
authors: I
authors: Vila
authors: Sylvie
authors: S
authors: Caspar-Bauguil
authors: Katie
authors: K
authors: Louche
authors: Marie-Adeline
authors: MA
authors: Marques
authors: Aline
authors: A
authors: Mairal
authors: Marie-Laure
authors: ML
authors: Renoud
authors: Jean
authors: J
authors: Galitzky
authors: Cecilia
authors: C
authors: Holm
authors: Etienne
authors: E
authors: Mouisel
authors: Claire
authors: C
authors: Thalamas
authors: Nathalie
authors: N
authors: Viguerie
authors: Thierry
authors: T
authors: Sulpice
authors: Rémy
authors: R
authors: Burcelin
authors: Peter
authors: P
authors: Arner
authors: Dominique
authors: D
authors: Langin
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000187:drug effects* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D005947:Glucose; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects*; D008066:Lipolysis / Q000187:drug effects; D008297:Male; D051379:Mice; D008875:Middle Aged; D009525:Niacin / Q000494:pharmacology; D002787:Sterol Esterase / Q000378:metabolism; D055815:Young Adult
chemical_list: D009525:Niacin; D002787:Sterol Esterase; D005947:Glucose