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Hypophagia and Metabolic Adaptations in Mice with Defective ATGL-Mediated Lipolysis Cause Resistance to HFD-Induced Obesity

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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 Renate Schreibera,1, Peter Hofera, Ulrike Taschlera, Peter J. Vosholb, Gerald N. Rechbergera, Petra Kotzbecka, Doris Jaegera, Karina Preiss-Landla, Caleb C. Lordc, J. Mark Brownc, Guenter Haemmerlea, Robert Zimmermanna, Antonio Vidal-Puigb, and Rudolf Zechnera,1 aInstitute of Molecular Biosciences, University of Graz, 8010 Graz, Austria; bInstitute of Metabolic Science, Metabolic Disease Unit, Medical Research Council, Metabolic Research Laboratories, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom; and cDepartment of Pathology, Section of Lipid Sciences, School of Medicine, Wake Forest University, Winston-Salem, NC 27157 Edited by Roger H. Unger, Touchstone Center for Diabetes Research, University of Texas Southwestern, Dallas, TX, and approved September 24, 2015 (received for review August 13, 2015) Adipose triglyceride lipase (ATGL) initiates intracellular triglyceride lipase (MGL) hydrolyze all three ester bonds of TGs in a stepwise (TG) catabolism. In humans, ATGL deficiency causes neutral lipid manner to yield FAs and glycerol (4). Lipolysis is an exquisitely storage disease with myopathy (NLSDM) characterized by a regulated process. Food deprivation initiates lipolysis through the systemic TG accumulation. Mice with a genetic deletion of ATGL hormonal activation of adipocytes by catecholamines or natriuretic (AKO) also accumulate TG in many tissues. However, neither peptides, activation of protein kinases A or G, downstream phos- NLSDM patients nor AKO mice are exceedingly obese. This phorylation of multiple proteins of the lipolytic pathway, and release phenotype is unexpected considering the importance of the of coactivator proteins such as comparative gene identification-58 enzyme for TG catabolism in white adipose tissue (WAT). In this (CGI-58) (4, 5). These events, in turn, strongly activate ATGL and study, we identified the counteracting mechanisms that prevent HSL resulting in efficient TG hydrolysis. Because lipid synthesis and lipid catabolism are opposing met- excessive obesity in the absence of ATGL. We used “healthy” AKO abolic pathways using quite different modes of regulation, they mice expressing ATGL exclusively in cardiomyocytes (AKO/cTg) to were historically seen as uncoupled processes. However, accumu- circumvent the cardiomyopathy and premature lethality observed lating evidence suggested that a link exists between anabolic and in AKO mice. AKO/cTg mice were protected from high-fat diet catabolic lipid pathways (6–10). For example, the transcription of (HFD)-induced obesity despite complete ATGL deficiency in WAT genes involved in both processes is activated by the adipogenic and normal adipocyte differentiation. AKO/cTg mice were highly nuclear receptor PPAR-γ (4, 11). Furthermore, both humans and insulin sensitive under hyperinsulinemic-euglycemic clamp condi- mice lacking ATGL are not, or only moderately, obese. Patients tions, eliminating insulin insensitivity as a possible protective mecha- with mutations in the gene coding for ATGL [patatin-like phos- nism. Instead, reduced food intake and altered signaling by peroxisome pholipase containing protein 2 (PNPLA2)] suffer from cardiomy- proliferator-activated receptor-gamma (PPAR-γ) and sterol regulatory opathy and muscle weakness but have normal fat mass (12). element binding protein-1c in WAT accounted for the phenotype. Similarly, mice lacking ATGL because of a targeted deletion of These adaptations led to reduced lipid synthesis and storage in WAT Pnpla2 (AKO) also exhibit a severe cardiac defect leading to of HFD-fed AKO/cTg mice. Treatment with the PPAR-γ agonist rosigli- tazone reversed the phenotype. These results argue for the existence Significance of an adaptive interdependence between lipolysis and lipid synthesis. Pharmacological inhibition of ATGL may prove useful to prevent HFD- Themassofwhiteadiposetissue(WAT) in an organism is tightly induced obesity and insulin resistance. controlled by the balance of triglyceride (TG) synthesis and catab- olism. Here, we show that these opposing pathways communicate. ATGL | PPAR-gamma | lipolysis | lipogenesis | obesity TG catabolism by adipose triglyceride lipase (ATGL) activates per- oxisome proliferator-activated receptor gamma (PPAR-γ), a crucial ssentially all organisms face the problem of continuous en- transcription factor for TG synthesis and storage in WAT. Conse- Eergy demand in an environment of irregular food supply. To quently, ATGL deficiency in WAT not only impairs TG break- overcome this dilemma, metazoan organisms developed special down, but also PPAR-γ–driven TG formation. This decrease in TG storage depots for substrates that are used for energy production. synthesis leads to a paradoxical resistance to high fat diet-induced In vertebrates, by far the most efficient energy reservoir is adi- obesity in mice lacking ATGL. Interdependence of lipid catabo- pose tissue (1). This highly expandable organ is able to store all lism and synthesis provides a rational explanation for the lack of major nutritional components (fat, carbohydrates, and proteins) obesity in ATGL-deficient mice and humans and identifies ATGL as triglycerides (TGs). Adipose tissue mass and TG content de- inhibition as potential treatment target to prevent diet-induced pend on the balance of anabolic and catabolic pathways. Lipid obesity and insulin resistance. storage in response to nutrient supply involves the generation of adipocytes (adipogenesis), the induction of fatty acid (FA) syn- Author contributions: R.S., G.H., R. Zimmermann, and R. Zechner designed research; R.S., P.H., U.T., P.J.V., G.N.R., P.K., D.J., K.P.-L., C.C.L., and J.M.B. performed research; A.V.-P. thesis from glucose and amino acids (de novo lipogenesis), and contributed new reagents/analytic tools; R.S., P.H., U.T., and P.J.V. analyzed data; R.S. and the synthesis of TGs (lipid synthesis). These processes are acti- R. Zechner wrote the paper; R.S. and R. Zechner conceived the hypothesis; and R.S. and vated by a complex transcriptional network involving CCAAT/ R. Zechner interpreted experimental results. enhancer-binding proteins (C/EBPs), sterol regulatory enhancer The authors declare no conflict of interest. binding proteins (SREBPs), and the heterodimer of peroxisome This article is a PNAS Direct Submission. proliferator-activated receptor-gamma (PPAR-γ) and retinoid-X Freely available online through the PNAS open access option. receptor (RXR) (2, 3). 1To whom correspondence may be addressed. Email: [email protected] or The opposing metabolic pathway of TG catabolism (lipolysis) [email protected]. requires activation of enzymes called lipases. Adipose TG lipase This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. (ATGL), hormone-sensitive lipase (HSL), and monoglyceride 1073/pnas.1516004112/-/DCSupplemental. 13850–13855 | PNAS | November 10, 2015 | vol. 112 | no. 45 www.pnas.org/cgi/doi/10.1073/pnas.1516004112 Downloaded by guest on September 30, 2021 premature death but are only moderately obese (13–15). This deficiency, the most pronounced differences were observed in mice benign adipose tissue phenotype is unexpected considering the fasted for 4 h. Under this condition, HFD-fed AKO/cTg mice had pivotal role of ATGL in TG catabolism and led us to hypoth- 23%, 52%, 72%, and 51% lower circulating glucose, FA, TG, and esize that ATGL-mediated TG hydrolysis regulates lipogenesis glycerol levels, respectively, than WT/cTg mice. Moreover, plasma and lipid synthesis by currently unknown mechanisms. insulin levels were reduced by 90% in AKO/cTg mice. In this study, we show that the absence of ATGL in mice fed a Extrapolating the results obtained from our studies on chow diet, high-fat diet (HFD) leads to reduced food intake, decreased lipid we hypothesized that AKO/cTg mice on HFD would develop a synthesis, and resistance to obesity. At the same time, the animals much more pronounced obesity than WT/cTg mice on HFD. But remain highly insulin sensitive. These results highlight a previously in contrast to our expectations, AKO/cTg mice fed a HFD accu- unrecognized interdependence between functional lipolysis and mulated less fat than age-matched WT/cTg mice (Fig. 1B). Mass of effective lipid biogenesis and suggest that inhibition of ATGL in gWAT and iWAT were 30% and 25% lower in AKO/cTg than in adipose tissue may ameliorate HFD-induced obesity as well as in- WT/cTg animals. Unlike WAT depots, iBAT mass remained en- sulin resistance (IR) and type-2 diabetes. larged in AKO/cTg mice (3.6-fold). Adipocyte size in gWAT of AKO/cTg mice fed a chow diet was bigger than in WT/cTg but Results smaller when animals were fed a HFD (Fig. S1D). Overall, on AKO/cTg Mice Are Protected from HFD-Induced Obesity. To assess HFD, AKO/cTg mice had less total body fat (−22%) and lean mass whether lipolysis affects HFD-induced obesity, we initially fed 4- to (−9%, not significant) as well as lower total body weight (−15%) 6-wk-oldAKOmiceaHFDfor8wk.AKOmiceonHFDdied than WT/cTg (Fig. 1B). Tibia length did not differ between earlier than chow-fed AKO mice. On HFD, 50% of AKO mice genotypes, indicating that the lower body weight in AKO/cTg died at the age of 11–13 wk versus 16–17 wk on chow (Fig. S1A;ref. mice was not due to retarded growth (17.08 ± 0.47 mm for 13). We also observed after 6 wk of HFD and prior to death that WT/cTg and 17.33 ± 0.56 mm for AKO/cTg). Consistent with re- AKO mice gained less body weight (−9%) and gonadal white ad- duced fat mass, plasma leptin levels were 53% lower in HFD-fed iposetissue(gWAT)mass(−43%; Fig. S1 B and C) than WT mice AKO/cTgmicethaninHFD-fedWT/cTg(Table S1). Plasma adi- on HFD. Nonetheless, the severe morbidity and early mortality ponectin concentrations were in the normal range in both geno- observed in these animals placed the physiological relevance of these types. Although fasting plasma insulin levels were significantly lower results in question and precluded meaningful metabolic studies in- in AKO/cTg mice than in WT/cTg mice, they were similar in both cluding hyperinsulinemic-euglycemic clamp experiments.
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