Adipocyte SIRT1 controls systemic insulin sensitivity by modulating macrophages in adipose tissue

Abstract

Adipose tissue inflammation, characterized by augmented infiltration and altered polarization of macrophages, contributes to insulin resistance and its associated metabolic diseases. The NAD-dependent deacetylase SIRT1 serves as a guardian against metabolic disorders in multiple tissues. To dissect the roles of SIRT1 in adipose tissues, metabolic phenotypes of mice with selective ablation of SIRT1 in adipocytes and myeloid cells were monitored. Compared to myeloid-specific SIRT1 depletion, mice with adipocyte-selective deletion of SIRT1 are more susceptible to diet-induced insulin resistance. The phenotypic changes in adipocyte-selective SIRT1 knockout mice are associated with an increased number of adipose-resident macrophages and their polarization toward the pro-inflammatory M1 subtype. Mechanistically, SIRT1 in adipocytes modulates expression and secretion of several adipokines, including adiponectin, MCP-1, and interleukin 4, which in turn alters recruitment and polarization of the macrophages in adipose tissues. In adipocytes, SIRT1 deacetylates the transcription factor NFATc1 and thereby enhances the binding of NFATc1 to the gene promoter. These findings suggest that adipocyte SIRT1 controls systemic glucose homeostasis and insulin sensitivity via the cross talk with adipose-resident macrophages.

Monounsaturated Fatty Acids in a High‐Fat Diet and Niacin Protect from White Fat Dysfunction in the Metabolic Syndrome

“…By concordant gene expression patterns, we have been able to segregate the polarization state of adipose macrophages close to an M1 status with milk cream and to an M2 status with olive oil either without or with EPA and DHA supplementation, reconcilable with lower transcriptional activities of pro‐inflammatory genes and higher transcriptional activities of anti‐inflammatory genes (IL‐10 and IL‐4) in WAT of mice fed with olive‐oil‐based HFDs. IL‐4 expression is induced by SIRT1 in adipocytes and via PPARγ supports the alternative activation M2 in adipose macrophages . Our study further points to a low adipose inflammation and thereby the safeguard of WAT homeostasis when, in combination with niacin, the predominant dietary fat during HFD‐induced obesity and metabolic syndrome is olive oil.…”

“…Similar to what is seen with NAMPT, the expression of adipose sirtuins (SIRTs) that use NAD + as their substrate is lower in obese subjects and decreases in mice on HFD . The reputation of SIRTs in integrating metabolism and immunity is emphasized by the increased number of adipose‐resident and M1 macrophages found in mice with adipocyte‐selective SIRT1 deletion . Furthermore, the fuel of NAD + for SIRTs is severely compromised by other NAD + consumers such as the cluster of differentiation 38 (CD38) whose deletion phenocopies the condition of SIRT1 activation in WAT .…”

“…Upon activation by increased intracellular NAD + levels, SIRT1 and SIRT3 culminate in enhancing energy expenditure and counteracting the weight gain and obesity‐related metabolic abnormalities associated with the ingestion of a lard‐based HFD in mice . Adipose SIRT1 expression improves insulin sensitivity in humans and mice, though the role of SIRT3 on mitochondrial function in adipocytes and whole‐body metabolism remains a controversy . We analyzed gene expression of SIRT1 and SIRT3 in WAT of niacin‐treated mice and found that the HFD based on milk cream was repressive for both genes while HFDs based on olive oil promoted their transcriptional activities, consistent with the selective effects of such HFDs on the levels of adipose NAD + .…”

“…This is crucial to avoid the advance of adipose tissue macrophage‐driven inflammation under sustained conditions of metabolic pressure induced by dietary fat overload. Worthy of noting is the fact that the number of adipose‐resident and M1 macrophages was recently noticed to increase in mice with selective ablation of SIRT1 in adipocytes, indicating that NAD + biosynthesis and signaling could share an underlying link with phenotypic changes of adipose macrophages. The diversity and heterogeneity of macrophages in WAT and other tissues are highly dependent on local microenvironments and currently envisioned as plastic cell populations with a continuum of functional phenotypes, the extremes of which are called classic or M1 and alternative or M2 macrophages, with obesity‐ and metabolic‐syndrome‐associated cues introducing new unwelcome subset variants such as metabolic activated and oxidized macrophages toward the M1 end of the activation spectrum .…”

Micro‐environment and intracellular metabolism modulation of adipose tissue macrophage polarization in relation to chronic inflammatory diseases

“…10,22 This finding was supported by Aimin et al, who have found that disruption of glucose homeostasis by specific inactivation of SIRT1, a key regulator for glucose metabolism in adipocytes, exacerbates macrophage infiltration and the pro-inflammatory M1 polarization of ATMs, which, at least in part, leads to the aggravation of systemic glucose intolerance and insulin resistance at the early stage in obese mice, suggesting a necessary relationship between the glucose metabolism in AT and ATM polarization. 23 In addition, treating ATMs with glucose induced a "metabolically activated" pro-inflammatory phenotype in obese humans or mice that is positively correlated with adiposity. 10 More recently, emerging studies indicated that the abnormal glucose metabolism in macrophages can dramatically accelerate the development of CVDs.…”