Genetic control of ATGL-mediated lipolysis modulates adipose triglyceride stores in leptin-deficient mice

摘要: Obesity, defined as the accumulation of triglycerides within adipocytes, leads to increased body fat content and exacerbates susceptibility type 2 diabetes, cardiovascular dysfunction, cancer (1–3). Individual obesity is variable integrates both environmental genetic factors (4). Because increasing prevalence worldwide, identification tissues molecules target should be a high priority expand list potential therapeutic modalities (5). The adipose tissue-derived hormone leptin its downstream signaling pathways play central role in obesity, or receptor deficiency provokes morbid (6–9). In addition, resistance has been implicated ontogenesis (10). Most receptor-mediated are active mainly nervous system (11), principally localized hypothalamus, decrease food intake, increase energy expenditure, inhibit lipogenesis, maintain normal glucose homeostasis (12). Consistent with these pleiotropic functions leptin, studies on regulation composition centered upon mechanisms mediated by receptor. Alternatively, identifying that regulate mass independently would interest design therapies aimed combat obesity. We others have reported mouse inbred strains carry specific sets variants promoting significant variation expression leptin-deficient phenotype (13, 14). Thus, regulatory independent can control metabolism, mapping quantitative trait loci (QTL) using mice an ideal method such pathways. this setting, BALB/c background reduced adiposity when compared ob/ob prototypic C57BL/6J strain (15). However, functional bases for variant phenotypes were not thoroughly characterized. Here, we performed comprehensive analysis physiological mechanism(s) limit found relied improved oxidation. This operated through enhanced adipocyte lipolysis due intracellular activity triglyceride lipase (ATGL/PNPLA2/desnutrin). higher rate adipocytes sustains fatty acid oxidation mice. genome-wide QTL uncovered Lipq1 (for lipolytic line 1) chromosome associated fraction ATGL content. Interestingly, does alter intake. conclusion, our study supports leptin-independent rates regulating directly modifies balance macronutrient handling sufficient absence detectable changes intake expenditure.