Apoptosis inhibitor of macrophage (AIM) is required for obesity-associated recruitment of inflammatory macrophages into adipose tissue

Abstract

Infiltration of inflammatory macrophages into adipose tissues with the progression of obesity triggers insulin resistance and obesity-related metabolic diseases. We recently reported that macrophage-derived apoptosis inhibitor of macrophage (AIM) protein is increased in blood in line with obesity progression and is incorporated into adipocytes, thereby inducing lipolysis in adipose tissue. Here we show that such a response is required for the recruitment of adipose tissue macrophages. In vitro, AIM-dependent lipolysis induced an efflux of palmitic and stearic acids from 3T3-L1 adipocytes, thereby stimulating chemokine production in adipocytes via activation of toll-like receptor 4 (TLR4). In vivo administration of recombinant AIM to TLR4 -deficient ( TLR4 −/− ) mice resulted in induction of lipolysis without chemokine production in adipose tissues. Consistently, mRNA levels for the chemokines that affect macrophages were far lower in AIM -deficient ( AIM −/− ) than in wild-type ( AIM +/+ ) obese adipose tissue. This reduction in chemokine production resulted in a marked prevention of inflammatory macrophage infiltration into adipose tissue in obese AIM −/− mice, although these mice showed more advanced obesity than AIM +/+ mice on a high-fat diet. Diminished macrophage infiltration resulted in decreased inflammation locally and systemically in obese AIM −/− mice, thereby protecting them from insulin resistance and glucose intolerance. These results indicate that the increase in blood AIM is a critical event for the initiation of macrophage recruitment into adipose tissue, which is followed by insulin resistance. Thus, AIM suppression might be therapeutically applicable for the prevention of obesity-related metabolic disorders.

Deletion of Apoptosis Inhibitor of Macrophage (AIM)/CD5L Attenuates the Inflammatory Response and Infarct Size in Acute Myocardial Infarction

“…On the other hand, the activation of FAS, together with a decrease in FFAs, was observed in AIM −/− mice. It was reported that the inhibition of FAS activity due to AIM caused lipolysis in adipocytes without the activation of the cAMP/AMPK signaling pathway, hormone‐sensitive lipase, and adipose triglyceride lipase 11. Although it is known that there is an important interaction between AIM and FAS, the FAS activity might be attenuated by negative feedback from the increase in FFAs after MI.…”

The human CD5L/AIM-CD36 axis: A novel autophagy inducer in macrophages that modulates inflammatory responses

“…In mouse models and in humans, elevated levels of CD5L occur in conditions with inflammatory components such as LPSinduced fulminant hepatitis 20 , M. tuberculosis infection, 53 obesity, 25 liver cirrhosis, 12,13,62 and allergic asthma, 63 among others. Therefore, in these scenarios, high expression of CD5L may act in an autocrine fashion on MF to modulate inflammatory responses.…”

“…In this regard, this protein is incorporated into adipocytes, thereby modifying adipocyte lipid metabolism and thus resulting in the induction of adipocyte inflammation. 24,25 Interestingly, CD5L incorporation into adipocytes is mediated through scavenger receptor CD36. In fact, CD5L may also be internalized into MK through CD36, suggesting that this scavenger receptor may serve as its cellular receptor for endocytosis.…”

Insulin resistance pathogenesis in metabolic obesity

“…В гипертрофированных адипоцитах активно происходит липолиз. Образующиеся при этом СЖК, взаимодействуя с TLR-4, индуцируют экспрессию хемокинов, которые приводят к накоплению и активации макрофагов в ЖТ [30,55,56].…”

“…В гипертрофированных адипоцитах активно происходит липолиз. Образующиеся при этом СЖК, взаимодействуя с TLR-4, индуцируют экспрессию хемокинов, которые приводят к накоплению и активации макрофагов в ЖТ [30,55,56].При ожирении активированные макрофаги М1-типа (классически активированные) стимулируют лейкоцитарную инфильтрацию на фоне увеличения Th-1-, Th-17-и CD8+-Т-клеток и уменьшения макрофагов M2-типа (альтернативно активированные), Тreg и Th-2 клеток в ЖТ [57][58][59][60]. Учитывая тот факт, что макрофаги способствуют гипертрофии адипоцитов, следует признать, что при ожирении имеет место порочный круг с положительной обратной связью: гипертрофированные адипоциты продуцируют хемокины и их рецепторы, которые инициируют рекрутирование моноцитов/макрофагов в ЖТ.…”