Emerging evidence for beneficial macrophage functions in atherosclerosis and obesity-induced insulin resistance

Abstract

The discovery that obesity promotes macrophage accumulation in visceral fat led to the emergence of a new field of inquiry termed “immunometabolism”. This broad field of study was founded on the premise that inflammation and the corresponding increase in macrophage number and activity was a pathologic feature of metabolic diseases. There is abundant data in both animal and human studies that supports this assertation. Established adverse effects of inflammation in visceral fat include decreased glucose and fatty acid uptake, inhibition of insulin signaling, and ectopic triglyceride accumulation. Likewise, in the atherosclerotic plaque, macrophage accumulation and activation results in plaque expansion and destabilization. Despite these facts, there is an accumulating body of evidence that macrophages also have beneficial functions in both atherosclerosis and visceral obesity. Potentially beneficial functions that are common to these different contexts include the regulation of efferocytosis, lipid buffering, and anti-inflammatory effects. Autophagy, the process by which cytoplasmic contents are delivered to the lysosome for degradation, is integral to many of these protective biologic functions. The macrophage utilizes autophagy as a molecular tool to maintain tissue integrity and homeostasis at baseline (e.g., bone growth) and in the face of ongoing metabolic insults (e.g., fasting, hypercholesterolemia, obesity). Herein, we highlight recent evidence demonstrating that abrogation of certain macrophage functions, in particular autophagy, exacerbates both atherosclerosis and obesity-induced insulin resistance. Insulin signaling through mammalian target of rapamycin (mTOR) is a crucial regulatory node that links nutrient availability to macrophage autophagic flux. A more precise understanding of the metabolic substrates and triggers for macrophage autophagy may allow therapeutic manipulation of this pathway. These observations underscore the complexity of the field “immunometabolism”, validate its importance, and raise many fascinating and important questions for future study.

Docosahexaenoic Acid–Derived Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) With Anti-inflammatory Properties

“…The detection of DHAHLA and DHAHDHA in both mice and humans, and the emerging concept that the immune and metabolic systems are interconnected (17,26), strongly suggest the involvement of the novel lipids in the broad beneficial effects of n-3 PUFAs on health. Thus, in humans, in addition to their anti-inflammatory effects in WAT (see above), n-3 PUFAs attenuate systemic inflammatory processes (46), help to prevent cardiovascular disease (47), ameliorate nonalcoholic fatty liver disease (48), lower hypertriacylglycerolemia (49), and increase circulating adiponectin levels (50).…”

“…The obesity-associated WAT inflammation imposes adverse local as well as whole-body metabolic effects (1,2,11,(17)(18)(19). This inflammatory response is accompanied by macrophage repolarization to the proinflammatory (classically activated) M1 state, which negatively affects WAT functions (20) and could be counteracted using both dietary and pharmacological interventions (21,22).…”

“…This inflammatory response is accompanied by macrophage repolarization to the proinflammatory (classically activated) M1 state, which negatively affects WAT functions (20) and could be counteracted using both dietary and pharmacological interventions (21,22). Regarding the dietary influence, namely n-3 polyunsaturated FAs (PUFAs) of marine origin, which are considered to be healthy dietary constituents in individuals with diabetes (23) (see DISCUSSION), play an important role in the resolution of WAT inflammation (24)(25)(26)(27)(28) and probably potentiate beneficial functions of immune cells in WAT like efferocytosis or autophagy (17).…”

Metabolically Activated Adipose Tissue Macrophages Perform Detrimental and Beneficial Functions during Diet-Induced Obesity

“…In addition to producing inflammatory cytokines, ATMs have also been postulated to perform beneficial functions during diet-induced obesity (Fitzgibbons and Czech, 2016). They internalize excess free fatty acids (FFAs) released by insulin resistant adipocytes, thereby buffering metabolic tissues from the damage caused by ectopic accumulation of saturated FFAs.…”

Vasculature-associated adipose tissue macrophages dynamically adapt to inflammatory and metabolic challenges

“…It is thought that the myeloid cells found in the adipose tissue during diet-induced obesity (DIO) contribute to the pathogenesis of insulin resistance and the metabolic syndrome, by increasing their secretion of pro-inflammatory cytokines, such as TNFα. However, it is unclear how adipose immune cells mediate pathology, and what the possible roles of myeloid cells are in the steady state (Dalmas et al, 2011;Fitzgibbons and Czech, 2016;Lumeng, 2013;Wynn et al, 2013;Xu et al, 2013).…”