Autotaxin-LPA signaling contributes to obesity-induced insulin resistance in muscle and impairs mitochondrial metabolism

Abstract

Autotaxin (ATX) is an adipokine that generates the bioactive lipid, lysophosphatidic acid (LPA). ATX-LPA signaling has been implicated in diet-induced obesity and systemic insulin resistance. However, it remains unclear whether the ATX-LPA pathway influences insulin function and energy metabolism in target tissues, particularly skeletal muscle, the major site of insulin-stimulated glucose disposal. The objective of this study was to test whether the ATX-LPA pathway impacts tissue insulin signaling and mitochondrial metabolism in skeletal muscle during obesity. Male mice with heterozygous ATX deficiency (ATX) were protected from obesity, systemic insulin resistance, and cardiomyocyte dysfunction following high-fat high-sucrose (HFHS) feeding. HFHS-fed ATX mice also had improved insulin-stimulated AKT phosphorylation in white adipose tissue, liver, heart, and skeletal muscle. Preserved insulin-stimulated glucose transport in muscle from HFHS-fed ATX mice was associated with improved mitochondrial pyruvate oxidation in the absence of changes in fat oxidation and ectopic lipid accumulation. Similarly, incubation with LPA decreased insulin-stimulated AKT phosphorylation and mitochondrial energy metabolism in C2C12 myotubes at baseline and following palmitate-induced insulin resistance. Taken together, our results suggest that the ATX-LPA pathway contributes to obesity-induced insulin resistance in metabolically relevant tissues. Our data also suggest that LPA directly impairs skeletal muscle insulin signaling and mitochondrial function.

Whey Peptides Stimulate Differentiation and Lipid Metabolism in Adipocytes and Ameliorate Lipotoxicity-Induced Insulin Resistance in Muscle Cells

“…C2C12 myotubes were incubated for 18 h in the presence of whey and BSA peptides or their native (unhydrolyzed) protein controls. Concurrently, cells were incubated in the presence or absence of palmitate, which triggers lipotoxicity and insulin resistance [32]. In the absence of palmitate, insulin-stimulated phosphorylation of AKT at S473 was similar between myotubes incubated with WPH, BPI, and BPH, as evidenced by a 4-to 5-fold increase in AKT phosphorylation relative to no-insulin controls ( Figure 4A).…”

“…C2C12 myoblasts (ATCC) were grown and differentiated to myotubes as described [32]. Briefly, 5.0 × 10 5 cells were seeded in 60 mm plates and maintained in DMEM-HG supplemented with 10% FBS.…”

“…After 24 h, myoblasts were differentiated in DMEM-HG + 0.2% FBS. To induce insulin resistance, myotubes were incubated in DMEM (11966025, Thermo Fisher Scientific, Waltham, MA, USA) containing 5 mM glucose, 2% (w/v) fatty acid-free (FAF) BSA, and 0.4 mM sodium palmitate for 18 h, as described [32]. Control myotubes were cultured in the absence of palmitate.…”

“…Respiratory oxygen flux in 3T3-L1 adipocytes and C2C12 myotubes was measured in high-resolution using the Oxygraph-2k (OROBOROS Instruments, Innsbruck, Austria) as described [32]. Briefly, following incubation with whey proteins and peptides, cells were detached, resuspended at a concentration of 200,000 cells/mL, and permeabilized with 3 µg/mL digitonin.…”

Autotaxin and Breast Cancer: Towards Overcoming Treatment Barriers and Sequelae

“…ATX production increases in obesity, especially when adipose tissue is inflamed [24,30]. Inflamed adipose tissue increases the co-morbidities of insulin resistance, diabetes, dyslipidemia, hypertension, and atherosclerosis [96,97], and serum ATX levels positively correlates with insulin resistance in older obese adults [98]. These conditions are characterized by low plasma adiponectin concentrations [99] and LPA decreases adiponectin secretion [94].…”