Enhanced glycolysis and HIF-1α activation in adipose tissue macrophages sustains local and systemic interleukin-1β production in obesity

Abstract

During obesity, macrophages infiltrate the visceral adipose tissue and promote inflammation that contributes to type ii diabetes. evidence suggests that the rewiring of cellular metabolism can regulate macrophage function. However, the metabolic programs that characterize adipose tissue macrophages (ATM) in obesity are poorly defined. Here, we demonstrate that ATM from obese mice exhibit metabolic profiles characterized by elevated glycolysis and oxidative phosphorylation, distinct from ATM from lean mice. Increased activation of HIF-1α in AtM of obese visceral adipose tissue resulted in induction of IL-1β and genes in the glycolytic pathway. Using a hypoxia-tracer, we show that HIF-1α nuclear translocation occurred both in hypoxic and non-hypoxic AtM suggesting that both hypoxic and pseudohypoxic stimuli activate HIF-1α and its target genes in AtM during diet-induced obesity. Exposure of macrophages to the saturated fatty acid palmitate increased glycolysis and HIF-1α expression, which culminated in IL-1β induction thereby simulating pseudohypoxia. Using mice with macrophage-specific targeted deletion of HIF-1α, we demonstrate the critical role of HIF-1α-derived from macrophages in regulating ATM accumulation, and local and systemic IL-1β production, but not in modulating systemic metabolic responses. collectively, our data identify enhanced glycolysis and HIF-1α activation as drivers of low-grade inflammation in obesity. Obesity and its associated metabolic diseases, insulin resistance and type 2 diabetes, continue to increase in the United States and worldwide 1 , and fully effective therapies to combat this growing epidemic are lacking. Obesity gives rise to a state of chronic inflammation, which is causally linked to insulin resistance (IR) and type 2 diabetes 2-4. In obese mice and humans, there is a striking accrual of macrophages in visceral adipose tissue 5,6 , and these immune cells are key contributors to obesity-induced insulin resistance 2,7. Whereas adipose tissue macrophages (ATM) comprise approximately 10-15% of stromal cells in the lean adipose tissue, during high fat diet feeding the recruitment of monocytes into visceral adipose depots can drive macrophage accumulation up to 50% of all cells in obese adipose tissue 7. A number of factors, including adipocyte hypertrophy, increased extracellular lipid concentrations and oxidative stress are thought to drive expression of chemoattractant factors that recruit monocytes in the expanding adipose tissue 2,7. In this metabolically disturbed environment, the monocyte-derived macrophages take on an inflammatory phenotype that is distinct from those of macrophages residing in lean adipose tissue 8,9. These ATMs are a source of inflammatory cytokines, particularly TNFα 10 and IL-1β 11 , that sustain the local and systemic inflammation that contributes to insulin resistance [reviewed in 2 ], yet the mechanisms that drive metabolic inflammation and the pro-inflammatory ATM phenotype, remain poorly understood.

Elevated CCL2 causes Leydig cell malfunction in metabolic syndrome

“…As IL-1β is critically involved in the translation of obesity-related inflammation into diseases of adjacent organs (57-59), it is plausible to assume that the IL-1β derived from the adipose tissue contributes, at least in part, to the increased IL-1β level in the testes and to subsequent Leydig cell malfunction. Indeed, macrophages in the adipose tissue from obese mice showed elevated glycolysis and oxidative phosphorylation, which increased activation of HIF-1α and resulted in sustained local and systemic IL-1β production (60). Another potential source of IL-1β is the intratesticular cells, including macrophages and Leydig cells, that could be induced through either endocrine or paracrine signaling.…”

Revisiting the PD-1 pathway

“…Growing evidence suggests that hyperglycemia and cholesterolemia skew hematopoietic stem cells to enhance myelopoiesis and production of proinflammatory myeloid cells ( 128 , 129 ). Such enhanced myelopoiesis propagates inflammation from the bone marrow to the adipose tissue and the vasculature and contributes to the increased production of TNF-α, IL-6, IL-1, and C-reactive protein, leading to insulin resistance ( 130 , 131 ). Further, low-grade inflammation, persistent myelopoiesis, and MDSC expansion have been proposed as potent inducers of immunosenescence in age-related immune deficiency ( 132 ).…”

Rewiring of Lipid Metabolism in Adipose Tissue Macrophages in Obesity: Impact on Insulin Resistance and Type 2 Diabetes

“…Hypoxia provides a means for explaining several metabolic changes seen during obesity, as the hypoxia-inducible transcription factor-1α (Hif-1α) is implicated in glucose metabolism, inflammatory cytokine expression, adipocyte hypertrophy and death, among other gene programs [26,27]. Most importantly, it has a role in ATM activation, as myeloid-specific deletion of this transcription factor reduces ATM accumulation and IL-1β production [28].…”

“…In this context, adipose FA binding protein (FABP) was reported to play an important role in ceramide production and cell death in macrophages upon incubation with SFA (PA and stearic acid) [122]. Finally, PA is able to induce the expression of Hif-1α in macrophages even under normoxic conditions [28] and to promote pro-inflammatory cytokine expression. This might therefore provide another mechanism, independent of TLR4, for ATM activation during obesity.…”