Partial Inhibition of Adipose Tissue Lipolysis Improves Glucose Metabolism and Insulin Sensitivity Without Alteration of Fat Mass

Girousse, Amandine; Tavernier, Geneviève; Valle, Carine; Moro, Cédric; Mejhert, Niklas; Dinel, Anne Laure; Houssier, Marianne; Roussel, Bruno; Besse-Patin, Aurèle; Combes, Marion; Mir, Lucile; Monbrun, Laurent; Bézaire, Véronic; Prunet-Marcassus, Bénédicte; Waget, Aurélie; Vila, Isabelle K.; Caspar-Bauguil, Sylvie; Louche, Katie; Marqués, Marie-Adeline; Mairal, Aline; Renoud, Marie Laure; Galitzky, Jean; Holm, Cecilia; Mouisel, Etienne; Thalamas, Claire; Viguerie, Nathalie; Sulpice, Thierry; Burcelin, Rémy; Arner, Peter; Langin, Dominique

doi:10.1371/journal.pbio.1001485

Cited by 177 publications

(158 citation statements)

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“…Therefore, we assessed whether IR in WAT leads to decreased lipid synthesis and storage in HFD-fed AKO/cTg mice. GTT, ITT, and hyperinsulinemic/euglycemic clamp experiments, however, clearly showed that AKO/cTg mice were much more glucose tolerant and insulin sensitive than insulinresistant HFD-fed WT/cTg mice or mice lacking HSL (42) or MGL (43). Abolished HGP, increased muscle glucose uptake, and a pronounced antilipolytic WAT response to insulin confirmed that all classical insulin target tissues remained insulin sensitive in HFD-fed AKO/cTg mice and disproved the concept that IR prevented efficient lipid storage in this model.…”

Section: Discussionmentioning

confidence: 94%

Hypophagia and metabolic adaptations in mice with defective ATGL-mediated lipolysis cause resistance to HFD-induced obesity

Schreiber

Hofer

Taschler

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Adipose triglyceride lipase (ATGL) initiates intracellular triglyceride (TG) catabolism. In humans, ATGL deficiency causes neutral lipid storage disease with myopathy (NLSDM) characterized by a systemic TG accumulation. Mice with a genetic deletion of ATGL (AKO) also accumulate TG in many tissues. However, neither NLSDM patients nor AKO mice are exceedingly obese. This phenotype is unexpected considering the importance of the enzyme for TG catabolism in white adipose tissue (WAT). In this study, we identified the counteracting mechanisms that prevent excessive obesity in the absence of ATGL. We used "healthy" AKO mice expressing ATGL exclusively in cardiomyocytes (AKO/cTg) to circumvent the cardiomyopathy and premature lethality observed in AKO mice. AKO/cTg mice were protected from high-fat diet (HFD)-induced obesity despite complete ATGL deficiency in WAT and normal adipocyte differentiation. AKO/cTg mice were highly insulin sensitive under hyperinsulinemic-euglycemic clamp conditions, eliminating insulin insensitivity as a possible protective mechanism. Instead, reduced food intake and altered signaling by peroxisome proliferator-activated receptor-gamma (PPAR-γ) and sterol regulatory element binding protein-1c in WAT accounted for the phenotype. These adaptations led to reduced lipid synthesis and storage in WAT of HFD-fed AKO/cTg mice. Treatment with the PPAR-γ agonist rosiglitazone reversed the phenotype. These results argue for the existence of an adaptive interdependence between lipolysis and lipid synthesis. Pharmacological inhibition of ATGL may prove useful to prevent HFDinduced obesity and insulin resistance.E ssentially all organisms face the problem of continuous energy demand in an environment of irregular food supply. To overcome this dilemma, metazoan organisms developed special storage depots for substrates that are used for energy production. In vertebrates, by far the most efficient energy reservoir is adipose tissue (1). This highly expandable organ is able to store all major nutritional components (fat, carbohydrates, and proteins) as triglycerides (TGs). Adipose tissue mass and TG content depend on the balance of anabolic and catabolic pathways. Lipid storage in response to nutrient supply involves the generation of adipocytes (adipogenesis), the induction of fatty acid (FA) synthesis from glucose and amino acids (de novo lipogenesis), and the synthesis of TGs (lipid synthesis). These processes are activated by a complex transcriptional network involving CCAAT/ enhancer-binding proteins (C/EBPs), sterol regulatory enhancer binding proteins (SREBPs), and the heterodimer of peroxisome proliferator-activated receptor-gamma (PPAR-γ) and retinoid-X receptor (RXR) (2, 3).The opposing metabolic pathway of TG catabolism (lipolysis) requires activation of enzymes called lipases. Adipose TG lipase (ATGL), hormone-sensitive lipase (HSL), and monoglyceride lipase (MGL) hydrolyze all three ester bonds of TGs in a stepwise manner to yield FAs and glycerol (4). Lipolysis is an exquisitely regulated proce...

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Section: Discussionmentioning

confidence: 94%

Hypophagia and metabolic adaptations in mice with defective ATGL-mediated lipolysis cause resistance to HFD-induced obesity

Schreiber

Hofer

Taschler

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…One potential mechanism contributing to improved insulin sensitivity and glucose metabolism in Ad-GsKO mice is reduced lipolysis in adipose tissue resulting in lower circulating FFA levels. It is well established that FFAs, the major product of lipolysis, cause deleterious effects on insulin sensitive organs (32,33) and that genetic or pharmacologic inhibition of adipose tissue lipolysis in mice improves glucose metabolism and insulin sensitivity (29,34). Moreover, high lipolysis rate is associated with low insulin sensitivity in humans (34).…”

Section: Discussionmentioning

confidence: 99%

“…It is well established that FFAs, the major product of lipolysis, cause deleterious effects on insulin sensitive organs (32,33) and that genetic or pharmacologic inhibition of adipose tissue lipolysis in mice improves glucose metabolism and insulin sensitivity (29,34). Moreover, high lipolysis rate is associated with low insulin sensitivity in humans (34). The lower TG content in liver present in Ad-GsKO may also contribute to improved glucose metabolism in these mice.…”

Section: Discussionmentioning

confidence: 99%

G _s α deficiency in adipose tissue improves glucose metabolism and insulin sensitivity without an effect on body weight

Shrestha

Chen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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G s α, the G protein that transduces receptor-stimulated cAMP generation, mediates sympathetic nervous system stimulation of brown adipose tissue (BAT) thermogenesis and browning of white adipose tissue (WAT), which are both potential targets for treating obesity, as well as lipolysis. We generated a mouse line with G s α deficiency in mature BAT and WAT adipocytes (Ad-GsKO). Ad-GsKO mice had impaired BAT function, absent browning of WAT, and reduced lipolysis, and were therefore cold-intolerant. Despite the presence of these abnormalities, Ad-GsKO mice maintained normal energy balance on both standard and high-fat diets, associated with decreases in both lipolysis and lipid synthesis. In addition, Ad-GsKO mice maintained at thermoneutrality on a standard diet also had normal energy balance. Ad-GsKO mice had improved insulin sensitivity and glucose metabolism, possibly secondary to the effects of reduced lipolysis and lower circulating fatty acid binding protein 4 levels. G s α signaling in adipose tissues may therefore affect whole-body glucose metabolism in the absence of an effect on body weight. T he sympathetic nervous system (SNS) regulates energy homeostasis and adiposity through several mechanisms, including activation of nonshivering thermogenesis in brown adipose tissue (BAT), browning (formation of BAT-like "beige" cells) of white adipose tissue (WAT), and stimulation of lipolysis. Although these processes have been shown to be potential targets in treating obesity and diabetes (1-3), ablation of sympathetic nerves (4-6) or their main effectors (norepinephrine and epinephrine) (7) does not result in obesity or insulin resistance. Although mice lacking β adrenergic receptors (β-less mice) do develop obesity (8), it is likely that this effect is not due only to loss of β-adrenergic signaling in adipose tissue.The main mediator of SNS function in adipose tissues is G s α (9, 10), a ubiquitously expressed G protein α-subunit that in adipose tissue couples adrenergic and other receptors, such as the adenosine A2A receptor (11), to the generation of intracellular cAMP. We have previously generated adipose-specific G s α knockout mice (FGsKO) using fatty acid binding protein 4 (FABP4) (aP2)-cre and showed these mice to have significant early mortality and a severely lean phenotype (12). However, the usefulness of this model to examine the role of G s α in mature adipocytes is limited due to both the lack of specificity of FABP4-cre expression in adipose tissue and the presence of a severe defect in adipogenesis due to expression of FABP4, and therefore loss of G s α, during an early step in adipocyte differentiation.Adiponectin is a mature adipocyte marker expressed late in adipocyte differentiation (13). The more recent availability of adiponectin-cre mouse lines (14, 15) has enabled us to generate adipose-specific G s α knockout mice (Ad-GsKO) in which G s α deletion is restricted to mature adipocytes. Despite having loss of BAT function or browning of WAT, Ad-GsKO mice failed to develop obesity on either ...

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“…After a 2.5-h adaptation period, blood sampling was initiated at 13:00. Samples were drawn at 13:00, 14 7,15,30,45,60,90, and 120 min after glucose load. Samples (30-150 µl, with total loss <5% of blood volume) were collected in potassium-EDTA tubes and centrifuged.…”

Section: Surgical Preparationmentioning

confidence: 99%

Nicotinic acid timed to feeding reverses tissue lipid accumulation and improves glucose control in obese Zucker rats[S]

Kroon

Baccega

Olsen

et al. 2017

Journal of Lipid Research

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Partial Inhibition of Adipose Tissue Lipolysis Improves Glucose Metabolism and Insulin Sensitivity Without Alteration of Fat Mass

Abstract: Partial inhibition of adipose tissue lipolysis does not increase fat mass but improves glucose metabolism and insulin sensitivity through modulation of fatty acid turnover and induction of fat cell de novo lipogenesis.

Cited by 177 publications

References 50 publications

Hypophagia and metabolic adaptations in mice with defective ATGL-mediated lipolysis cause resistance to HFD-induced obesity

Hypophagia and metabolic adaptations in mice with defective ATGL-mediated lipolysis cause resistance to HFD-induced obesity

G _s α deficiency in adipose tissue improves glucose metabolism and insulin sensitivity without an effect on body weight

Nicotinic acid timed to feeding reverses tissue lipid accumulation and improves glucose control in obese Zucker rats[S]

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Partial Inhibition of Adipose Tissue Lipolysis Improves Glucose Metabolism and Insulin Sensitivity Without Alteration of Fat Mass

Abstract: Partial inhibition of adipose tissue lipolysis does not increase fat mass but improves glucose metabolism and insulin sensitivity through modulation of fatty acid turnover and induction of fat cell de novo lipogenesis.

Cited by 177 publications

References 50 publications

Hypophagia and metabolic adaptations in mice with defective ATGL-mediated lipolysis cause resistance to HFD-induced obesity

Hypophagia and metabolic adaptations in mice with defective ATGL-mediated lipolysis cause resistance to HFD-induced obesity

G s α deficiency in adipose tissue improves glucose metabolism and insulin sensitivity without an effect on body weight

Nicotinic acid timed to feeding reverses tissue lipid accumulation and improves glucose control in obese Zucker rats[S]

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G _s α deficiency in adipose tissue improves glucose metabolism and insulin sensitivity without an effect on body weight