In order to adapt to the daily and seasonal changes in caloric intake, metazoans have evolved adipose tissue specifically for dynamic storage and release of energy. Excessive or impaired energy storage in these adipose tissues can lead to obesity, lipodystrophy or cachexia, and damage the body’s balance. Adipose tissue is composed of fat cells that store fat, supportive stromal cells, and immune cells. Adipocytes dynamically accumulate or release lipids in the late embryonic and postnatal periods.
Stromal cells include tissue macrophages, which are closely associated with fat cells throughout the animal kingdom from fruit flies to humans. Milestone research has shown that under obesity, monocyte-derived macrophages are recruited into tissues through CCR2 (CC chemokine receptor type 2, CC chemokine receptor type 2) and produce cytokines. Such as tumor necrosis factor (TNF), which leads to systemic inflammation, ectopic lipid storage and insulin resistance. However, neither CCR2 nor monocytes seem to be able to regulate fat content or fat percentage on their own. Recent observations in several models indicate that macrophages may also control fat, although their actual functions and underlying cellular and molecular mechanisms are still poorly understood.
Macrophages are phagocytes, which can eliminate unsuitable cells, microorganisms and metabolic waste, and produce a large number of biologically active molecules and growth factors. Except for monocyte-derived macrophages, which are the shorter-lived offspring of vertebrate hematopoietic stem cells, most animals have longer-lived tissue macrophages. In mice, these cells originate from the early mesoderm erythromyeloid progenitor cells, and the erythromyeloid progenitor cells invade the embryo shortly after the gastrulation is formed. They are the basic cell type in the mesenchymal primordium of most organs. Resident macrophages have specific uses for tissues. For example, osteoclasts are essential for bone development and remodeling, while microglia in the central nervous system support the development of neural circuits, Kupffer cells clear blood particles and dying red blood cells in the liver, and alveolar macrophages The cells absorb surfactants and remove air pollutants and microorganisms from the respiratory tract.
Based on this, in a new study, researchers from the United States and Germany hypothesized that resident macrophages associated with fat storage cells may also support their functions. They used the presence of equivalent cell types and orthologous genes in Drosophila and mice to identify a conserved molecular mechanism that mediates the control of fat and energy storage by macrophages in metazoans.
Using a combination of genetic and pharmacological methods, these authors found that the lack of resident macrophages prevents wild-type mice and Ccr2-/- mice from being fed a high-fat diet and anorexia leptin receptor deficiency Lipid storage in fat cells in mice. In addition, the researchers observed that the lack of macrophages impaired lipid storage in newborn mice and fruit fly larvae. Therefore, they conducted genetic screening in Drosophila and found that the macrophage-derived PDGF/VEGF family growth factor Pvf3 and its receptor on fat body cells are necessary for the lipid storage of Drosophila larvae. Further, they identified PDGFcc, an ortholog of mouse Pvf3, which controls lipid storage in mouse fat cells. PDGFcc is produced by adipose tissue resident macrophages in a diet-regulated manner, and acts on the subcutaneous and visceral white adipocytes in a fat tissue-autonomous manner, thereby controlling the lipid storage in neonatal and adult mice. PDGFcc block or lack does not affect food intake and absorption, but leads to an increase in body energy expenditure. This increase is partly achieved by increasing thermogenesis of brown adipose tissue. This function of adipose tissue-resident macrophages is different from that of CCR2-dependent monocyte-derived macrophages, which mediate systemic inflammation and insulin resistance in obese mice, but do not produce PDGFcc.
In summary, these data confirm the evolutionary conserved function of adipose tissue-resident macrophages, which links energy intake with fat storage in adipocytes through the production of PDGFcc, and is independent of CCR2-dependent macrophage promotion Inflammation. By promoting energy storage rather than expenditure in neonatal and adult mice, PDGFcc produced by resident macrophages appears to modulate or buffer the systemic availability of lipids for metabolism. These findings may facilitate the design of drug interventions for obesity, lipodystrophy, and cachexia.
