Reduced oxidative capacity in macrophages results in systemic insulin resistance

Abstract

Oxidative functions of adipose tissue macrophages control the polarization of M1-like and M2-like phenotypes, but whether reduced macrophage oxidative function causes systemic insulin resistance in vivo is not clear. Here, we show that mice with reduced mitochondrial oxidative phosphorylation (OxPhos) due to myeloid-specific deletion of CR6-interacting factor 1 (Crif1), an essential mitoribosomal factor involved in biogenesis of OxPhos subunits, have M1-like polarization of macrophages and systemic insulin resistance with adipose inflammation. Macrophage GDF15 expression is reduced in mice with impaired oxidative function, but induced upon stimulation with rosiglitazone and IL-4. GDF15 upregulates the oxidative function of macrophages, leading to M2-like polarization, and reverses insulin resistance in ob/ob mice and HFD-fed mice with myeloid-specific deletion of Crif1. Thus, reduced macrophage oxidative function controls systemic insulin resistance and adipose inflammation, which can be reversed with GDF15 and leads to improved oxidative function of macrophages.

Brown Adipocytes Secrete GDF15 in Response to Thermogenic Activation

“…Therefore, the paracrine effects determined for brown adipocyte-released GDF15 in reducing proinflammatory activity in macrophages may be highly significant in the functional role of GDF15 as a brown adipokine. Our findings regarding the capacity of GDF15 to target macrophages and downregulate macrophage proinflammatory signals are consistent with previous reports (24,25) but contrast with others (33). In any case, our findings highlight the capacity of BAT to be a source of GDF15 with potential local action, as well as the presence of peripheral actions of GDF15, similar to previous reports in other tissues (34,35).…”

“…The release of GDF15 by brown adipocytes may be a direct mechanism to locally downregulate the proinflammatory activity of macrophages in association with enhanced BAT activity. Although noncentrally mediated actions of GDF15 on energy balance are controverted (37), our results are consistent with data obtained for healthy metabolic effects of GDF15 in rodent models of obesity and insulin resistance not attributable to altered food intake and involving a reduction in inflammation in adipose tissues (25).…”

“…We observed no effects of treating brown adipocytes with GDF15, even at pharmacological levels (treatment up to 1 μg/mL), either on adipogenic or thermogenesis‐related gene expression (Supporting Information Table S5). Considering the previous data showing the potential effects of GDF15 on macrophages and with a growing awareness of the role of macrophages infiltrating BAT in controlling the thermogenic activity of the tissue , we explored the potential paracrine actions of GDF15 in macrophages (Figure ). We found that GDF15 significantly repressed gene expression of proinflammatory genes such as TNF, MCP1 (also known as chemokine [C‐C motif] ligand 2 [CCL2]), and IL6 in RAW 264.7 macrophages previously induced to a proinflammatory, M1‐type phenotype, following treatment with LPS.…”

Growth differentiation factor-15 is associated with age-related monocyte immunosenescence

“…The reduced respiratory capacity we demonstrated in our previous study [5] may render monocytes unable to generate sufficient ATP under aerobic conditions, leading to cellular dysfunction, although currently this is speculative. Because GDF-15 is thought to be a biomarker for mitochondrial dysfunction [30,31] and indeed promotes mitochondrial function in macrophages [32], it is likely that GDF-15 is not causally-related to mitochondrial dysfunction in monocytes, but circulating levels of the protein may serve as a useful proxy measure for myeloid mitochondrial dysfunction.…”

HILPDA uncouples lipid storage in adipose tissue macrophages from inflammation and metabolic dysregulation

“…Accordingly, it is likely that the loss of ATGL inhibition is directly responsible for the enhanced oxidative capacity, reducing the total intracellular lipid load. In general, increased lipolysis as well as increased oxidative respiration are two traits essential for macrophage polarization towards alternative, M2-like phenotypes, which has been suggested to be protective in the context of adipose tissue inflammation [30][31][32] . Interestingly, in our experiments, increased oxidative respiration seemed a mere consequence following overactive ATGL-mediated lipolysis, and did not contribute to any antiinflammatory effects in the context of adipose tissue inflammation.…”