Hypophagia and metabolic adaptations in mice with defective ATGL-mediated lipolysis cause resistance to HFD-induced obesity.
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 HFD-induced obesity and insulin resistance.
['Schreiber|Renate|R|', 'Hofer|Peter|P|', 'Taschler|Ulrike|U|', 'Voshol|Peter J|PJ|', 'Rechberger|Gerald N|GN|', 'Kotzbeck|Petra|P|', 'Jaeger|Doris|D|', 'Preiss-Landl|Karina|K|', 'Lord|Caleb C|CC|', 'Brown|J Mark|JM|', 'Haemmerle|Guenter|G|', 'Zimmermann|Robert|R|', 'Vidal-Puig|Antonio|A|', 'Zechner|Rudolf|R|']
D000222:Adaptation, Physiological D000818:Animals D059305:Diet, High-Fat D005247:Feeding Behavior D008049:Lipase D008066:Lipolysis D051379:Mice D018345:Mice, Knockout D009765:Obesity D047495:PPAR gamma D010641:Phenotype
lipolysis obesity ATGL PPAR-gamma lipogenesis