Tumor Necrosis Factor-α Promotes Phosphoinositide 3-Kinase Enhancer A and AMP-Activated Protein Kinase Interaction to Suppress Lipid Oxidation in Skeletal Muscle

Abstract

Tumor necrosis factor-α (TNF-α) is an inflammatory cytokine that plays a central role in obesity-induced insulin resistance. It also controls cellular lipid metabolism, but the underlining mechanism is poorly understood. We report in this study that phosphoinositide 3-kinase enhancer A (PIKE-A) is a novel effector of TNF-α to facilitate its metabolic modulation in the skeletal muscle. Depletion of PIKE-A in C2C12 myotubes diminished the inhibitory activities of TNF-α on mitochondrial respiration and lipid oxidation, whereas PIKE-A overexpression exacerbated these cellular responses. We also found that TNF-α promoted the interaction between PIKE-A and AMP-activated protein kinase (AMPK) to suppress its kinase activity in vitro and in vivo. As a result, animals with PIKE ablation in the skeletal muscle per se display an upregulation of AMPK phosphorylation and a higher preference to use lipid as the energy production substrate under high-fat diet feeding, which mitigates the development of diet-induced hyperlipidemia, ectopic lipid accumulation, and muscle insulin resistance. Hence, our data reveal PIKE-A as a new signaling factor that is important for TNF-α–initiated metabolic changes in skeletal muscle.

Long intergenic non-protein coding RNA 00475 silencing acts as a tumor suppressor in glioma under hypoxic condition by impairing microRNA-449b-5p-dependent AGAP2 up-regulation

“…36 Also, when AGAP2 was depleted, the inhibitory effect of TNF-α on lipid oxidation was reversed. 37 Taken together, the current study indicated that LINC00475 was activated in hypoxic glioma tissues and cells, and LINC00475 up-regulated AGAP2 by interacting with miR-449b-5p in glioma cells. In addition, our findings demonstrated that LINC00475 silencing decreased the expression of FAK-regulated HIF-1α by inhibiting AGAP2, thereby suppressing invasion and migration in hypoxic glioma cells ( Figure 6).…”

“…36 Also, when AGAP2 was depleted, the inhibitory effect of TNF-α on lipid oxidation was reversed. 37 …”

Impact of TNF-α Inhibitors on Body Weight and BMI: A Systematic Review and Meta-Analysis

“…TNF-a unfolds its anorexigenic effects at the arcuate nucleus of the hypothalamus, which is a central regulator of energy homeostasis, by inducing the production a-melanocyte-stimulating hormone (a-MSH) and cocaine-and amphetamine-regulated transcript (CART) in proopiomelanocortin (POMC)-expressing neurons; additionally, it leads to a decreased production of the orexigenic signals agouti-related protein (AgRP) and neuropeptide Y (NPY) in AgRP-expressing neurons (Romanatto et al, 2007). As TNF-a has been shown to stimulate the intracellular AMP-activated protein kinase (AMPK) (Tse et al, 2017), which integrates orexigenic and anorexigenic signals within the arcuate nucleus (Minokoshi et al, 2004), we hypothesize that this mechanism might play a role in the upregulation of a-MSH and CART and the downregulation of AgRP and NPY. These molecular signals will be conveyed to the lateral hypothalamus and the paraventricular nucleus and thus lead to reduced appetite and weight loss (Claret et al, 2007).…”

Infliximab ameliorates tumor necrosis factor‐alpha‐induced insulin resistance by attenuating PTP1B activation in 3T3L1 adipocytes in vitro

“…TNF‐alpha is a cytokine with prominent actions in cell differentiation and apoptosis, inflammation, autoimmunity and recruitment of other immune cell types toward peripheral tissues . TNF‐alpha has been also shown to play a pivotal role in glucose homeostasis by promoting insulin resistance in mice and humans, especially in adipose tissue . In this sense, mRNA and protein levels of TNF‐alpha have been previously reported to elevate in visceral adipose tissue of high‐fat diet (HFD)‐fed mice and obese subjects that show increased insulin resistance .…”

“…[7][8][9] TNF-alpha has been also shown to play a pivotal role in glucose homeostasis by promoting insulin resistance in mice and humans, especially in adipose tissue. 10,11 In this sense, mRNA and protein levels of TNFalpha have been previously reported to elevate in visceral adipose tissue of high-fat diet (HFD)-fed mice and obese subjects that show increased insulin resistance. 12 Moreover, TNF-alpha-deficient mice are protected against insulin resistance development, 13 while also TNF-alpha directly induces insulin resistance in 3T3L1 adipocytes in vitro.…”