Adipose Triglyceride Lipase Deficiency Causes Tissue-specific Changes in Insulin Signaling

Abstract

Triacylglycerol accumulation in insulin target tissues is associated with insulin resistance. Paradoxically, mice with global targeted deletion of adipose triglyceride lipase (ATGL), the ratelimiting enzyme in triacylglycerol hydrolysis, display improved glucose tolerance and insulin sensitivity despite triacylglycerol accumulation in multiple tissues. To determine the molecular mechanisms for this phenotype, ATGL-deficient (ATGL ؊/؊ ) and wild-type mice were injected with saline or insulin (10 units/ kg, intraperitoneally), and then phosphorylation and activities of key insulin-signaling proteins were determined in insulin target tissues (liver, adipose tissue, and muscle). Insulin signaling and/or glucose transport was also evaluated in isolated adipocytes and skeletal muscle ex vivo. In ATGL ؊/؊ mice, insulinstimulated phosphatidylinositol 3-kinase and Akt activities as well as phosphorylation of critical residues of IRS1 (Tyr(P)-612) and Akt (Ser(P)-473) were increased in skeletal muscle in vivo. Insulin-stimulated phosphatidylinositol 3-kinase activity and total insulin receptor and insulin receptor substrate 1, but not other parameters, were also increased in white adipose tissue in vivo. In contrast, in vivo measures of insulin signaling were decreased in brown adipose tissue and liver. Interestingly, the enhanced components of insulin signaling identified in skeletal muscle and white adipose tissue in vivo and their expected downstream effects on glucose transport were not present ex vivo. ATGL deficiency altered intramyocellular lipids as well as serum factors known to influence insulin sensitivity. Thus, skeletal muscle, rather than other tissues, primarily contributes to enhanced insulin sensitivity in ATGL ؊/؊ mice in vivo despite triacylglycerol accumulation, and both local and systemic factors contribute to tissue-specific effects of global ATGL deficiency on insulin action. Triacylglycerols (TAGs)4 are the predominant form of energy storage in animals. The ability to store and release this energy in response to variable energy availability requires a carefully regulated balance between TAG synthesis and hydrolysis. In the setting of chronic energy excess, however, TAGs and other lipid metabolites accumulate in adipose tissue as well as in metabolically relevant non-adipose tissues where they have been proposed to contribute to cellular dysfunction via a process known as lipotoxicity (1-3). Indeed, intracellular TAG accumulation has been repeatedly associated with metabolic dysfunction, a relationship that is particularly strong for insulin resistance (1-3). Despite this strong association, however, intracellular TAG accumulation is not always associated with insulin resistance (4) and may even be associated with insulin sensitivity, as is the case with highly trained endurance athletes (the so-called "athlete paradox") (5). Thus, the contribution of intracellular TAGs and TAG metabolism per se to lipotoxicity remains controversial. What is clear is that lipid-induced insulin resistance is a major ...

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

“…The increased fat mass in AKO/cTg mice led to a moderately higher body weight compared with WT/cTg. These findings are concordant with our earlier conclusion that defective lipolysis leads to increased adiposity in chow-fed mice (13,14).…”

“…premature death but are only moderately obese (13)(14)(15). This benign adipose tissue phenotype is unexpected considering the pivotal role of ATGL in TG catabolism and led us to hypothesize that ATGL-mediated TG hydrolysis regulates lipogenesis and lipid synthesis by currently unknown mechanisms.…”

Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism

“…However, our results clearly show substantial increases in both DAGs and ceramides, and yet no detriments to insulin signaling. This result is at first counterintuitive; however, other reports have found similar increases in lipotoxic species without induction of insulin resistance, including the well-known athlete's paradox (31)(32)(33)(34). Elevated DAGs have been found in endurance athletes with high insulin sensitivity (35).…”

Reduced Expression of Adipose Triglyceride Lipase Enhances Tumor Necrosis Factor α-induced Intercellular Adhesion Molecule-1 Expression in Human Aortic Endothelial Cells via Protein Kinase C-dependent Activation of Nuclear Factor-κB

“…Although the absence of ATGL would be expected to reduce both TG hydrolysis and other lipid metabolites, DAG concentrations were, surprisingly, increased in ATGL knockout mice (30). We found that PKC was already activated before TNF␣ stimulation in ATGL knockdown HAECs (Fig.…”