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Prenatal adipose tissue development affects body composition and growth trajectory in early infancy, therefore it is a key determinant of adiposity in childhood. Childhood overweight and obesity increase the probability of being obese as an adult. After birth and in adulthood, adipose tissue macrophages (ATMs) are relevant constituents of the fat depots, and they are necessary for physiological adipose tissue development and fat metabolism. In obesity, however, ATMs may induce chronic inflammation leading to insulin resistance, pancreatic beta cell damage and self-immunity. Despite being relevant regulators of adipose tissue development and functioning, it is unknown whether ATMs are present in the fetal adipose tissue, therefore it is elusive whether they may affect the prenatal establishment of fat depots. Here we studied the distribution of ATMs in the human fetus between gestational weeks 17 and 38 and labeled ATMs in the early postnatal life. We found that CD45 + /CD14 + /CD68 + ATMs infiltrated the fetal adipose tissue from the 17th week of gestation and remained persistent throughout the second and third trimesters. ATMs were phagocytic in the neonate and expressed interleukin-6, along with other pro-inflammatory gene products. These findings show that ATMs colonize the adipose tissue early in gestation, raising the possibility that intrauterine ATM-adipocyte communication may exist, eventually allowing ATMs to affect prenatal adipose tissue development.

Adipose tissue inflammation is a key factor leading to obesity-associated immune disorders, such as insulin resistance, beta cell loss in the pancreatic islets, meta-inflammation, and autoimmunity. Inhibiting adipose tissue inflammation is considered a straightforward approach to abrogate these diseases. However, recent findings show that certain pro-inflammatory cytokines are essential for the proper differentiation and functioning of adipocytes. Lipolysis is stimulated, and the thermogenic competence of adipocytes is unlocked by interleukin-6 (IL-6), a cytokine that was initially recognized as a key trigger of adipose tissue inflammation. Coherently, signal transducer and activator of transcription 3 (STAT3), which is a signal transducer for IL-6, is necessary for thermogenic adipocyte development. Given the impact of thermogenic adipocytes in increasing energy expenditure and reducing body adiposity, functions of IL-6 in the adipose tissue have gained attention recently. In this review, we show that IL-6 signaling may protect from excess fat accumulation by stimulating thermogenesis in adipocytes., Competing Interests: The authors declare no conflicts of interest.

In obesity, adipose tissue macrophages (ATMs) are abundant immune cells in the adipose tissue and are known as inducers of metabolic inflammation that may lead to insulin resistance and immune disorders associated with obesity. However, much less is known about the ontogeny and physiological functions of ATMs in lean adipose tissue. ATMs are present at birth and actively participate in the synthesis of mediators that induce lipolysis, mitobiogenesis, and thermogenesis in adipocytes. Later in life ATMs limit the thermogenic competence of the adipocytes and favor lipid storage. ATMs respond to lipid overload of adipocytes in obesity with a sequence of pro-inflammatory events, including inflammasome activation and pyroptosis, as well as stimulation of nuclear factor kappa B and interferon regulatory factors that evoke an uncontrolled inflammation. ATMs are life-long constituents of the adipose tissue and hence signals that control ATM development and ATM-adipocyte interactions determine adipose tissue health., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Adipose tissue macrophages (ATMs) play key roles in metabolic inflammation, insulin resistance, adipose tissue fibrosis, and immune disorders associated with obesity. Research on ATM biology has mostly been conducted in the setting of adult obesity, since adipocyte hypertrophy is associated with a significant increase in ATM number. Signals that control ATM activation toward a proinflammatory or a proresolving phenotype also determine the developmental program and lipid metabolism of adipocytes after birth. ATMs are present at birth and actively participate in the synthesis of mediators, which induce lipolysis, mitobiogenesis, and mitochondrial uncoupling in adipocytes. ATMs in the newborn and the infant promote a lipolytic and fatty acid oxidizing adipocyte phenotype, which is essential to support the lipid-fueled metabolism, to maintain nonshivering thermogenesis and counteract an excessive adipose tissue expansion. Since adipose tissue metabolism in the early postnatal life determines obesity status in adulthood, early-life ATM functions may have a life-long impact., (© 2022 The Authors. Journal of Leukocyte Biology published by Wiley Periodicals LLC on behalf of Society for Leukocyte Biology.)

Breastfeeding is a unique and defining behavior of mammals and has a fundamental role in nourishing offspring by supplying a lipid-rich product that is utilized to generate heat and metabolic fuel. Heat generation from lipids is a feature of newborn mammals and is mediated by the uncoupling of mitochondrial respiration in specific fat depots. Breastfeeding and thermogenic adipose tissue have a shared evolutionary history: both have evolved in the course of homeothermy evolution; breastfeeding mammals are termed "thermolipials", meaning "animals with warm fat". Beyond its heat-producing capacity, thermogenic adipose tissue is also necessary for proper lipid metabolism and determines adiposity in offspring. Recent advances have demonstrated that lipid metabolism in infants is orchestrated by breast milk lipid signals, which establish mother-to-child signaling and control metabolic development in the infant. Breastfeeding rates are declining worldwide, and are paralleled by an alarming increase in childhood obesity, which at least in part may have its roots in the impaired metabolic control by breast milk lipid signals.

The safe removal of apoptotic debris by macrophages-often referred to as efferocytosis-is crucial for maintaining tissue integrity and preventing self-immunity or tissue damaging inflammation. Macrophages clear tissues of hazardous materials from dying cells and ultimately adopt a pro-resolving activation state. However, adipocyte apoptosis is an inflammation-generating process, and the removal of apoptotic adipocytes by so-called adipose tissue macrophages triggers a sequence of events that lead to meta-inflammation and obesity-associated metabolic diseases. Signals that allow apoptotic cells to control macrophage immune functions are complex and involve metabolites released by the apoptotic cells and also metabolites produced by the macrophages during the digestion of apoptotic cell contents. This review provides a concise summary of the adipocyte-derived metabolites that potentially control adipose tissue macrophage immune functions and, hence, may induce or alleviate adipose tissue inflammation.

This chapter describes a technique that can be used to isolate adipose tissue macrophages (ATMs) from the visceral white adipose tissue. Nevertheless, this technique can also be used to isolate ATMs from subcutaneous white adipose tissue and brown adipose tissue from mouse, human subcutaneous fat depot, and also from the fat body of the toad Xenopus. We detail the flow-cytometric gating strategy that has been developed to identify ATM population, and we describe the isolation of RNA from this population and its use for gene expression profiling. Finally, we describe in vitro culture of ATMs for downstream applications.

ATMs have a metabolic impact in mammals as they contribute to metabolically harmful AT inflammation. The control of the ATM number may have therapeutic potential; however, information on ATM ontogeny is scarce. Whereas it is thought that ATMs develop from circulating monocytes, various tissue-resident Mϕs are capable of self-renewal and develop from BM-independent progenitors without a monocyte intermediate. Here, we show that amphibian AT contains self-renewing ATMs that populate the AT before the establishment of BM hematopoiesis. Xenopus ATMs develop from progenitors of aVBI. In the mouse, a significant amount of ATM develops from the yolk sac, the mammalian equivalent of aVBI. In summary, this study provides evidence for a prenatal origin of ATMs and shows that the study of amphibian ATMs can enhance the understanding of the role of the prenatal environment in ATM development., (© The Author(s).)

The quantity and activation state of adipose tissue macrophages (ATMs) impact the development of obesity-induced metabolic diseases. Appetite-controlling hormones play key roles in obesity; however, our understanding of their effects on ATMs is limited. Here, we have shown that human and mouse ATMs express NPFFR2, a receptor for the appetite-reducing neuropeptide FF (NPFF), and that NPFFR2 expression is upregulated by IL-4, an M2-polarizing cytokine. Plasma levels of NPFF decreased in obese patients and high-fat diet-fed mice and increased following caloric restriction. NPFF promoted M2 activation and increased the proliferation of murine and human ATMs. Both M2 activation and increased ATM proliferation were abolished in NPFFR2-deficient ATMs. Mechanistically, the effects of NPFF involved the suppression of E3 ubiquitin ligase RNF128 expression, resulting in enhanced stability of phosphorylated STAT6 and increased transcription of the M2 macrophage-associated genes IL-4 receptor α (Il4ra), arginase 1 (Arg1), IL-10 (Il10), and alkylglycerol monooxygenase (Agmo). NPFF induced ATM proliferation concomitantly with the increase in N-Myc downstream-regulated gene 2 (Ndrg2) expression and suppressed the transcription of Ifi200 cell-cycle inhibitor family members and MAF bZIP transcription factor B (Mafb), a negative regulator of macrophage proliferation. NPFF thus plays an important role in supporting healthy adipose tissue via the maintenance of metabolically beneficial ATMs.

The stromal vascular fraction (SVF) of adipose tissue in rodents and primates contains mesenchymal stem cells and immune cells. SVF cells have complex metabolic, immune and endocrine functions with biomedical impact. However, in other mammals, the amount of data on SVF stem cells is negligible and whether the SVF hosts immune cells is unknown. In this study, we show that the SVF is rich in immune cells, with a dominance of adipose tissue macrophages (ATMs) in cattle (Bos primigenius taurus), domestic goat (Capra aegagrus hircus), domestic sheep (Ovis aries), domestic cat (Felis catus) and domestic dog (Canis familiaris). ATMs of these species are granulated lysosome-rich cells with lamellipodial protrusions and express the lysosome markers acid phosphatase 5 (ACP-5) and Mac-3/Lamp-2. Using ACP-5 and Mac-3/Lamp-2 as markers, we additionally detected ATMs in other species, such as the domestic horse (Equus ferus caballus), wild boar (Sus scrofa) and red fox (Vulpes vulpes). Feline and canine ATMs also express the murine macrophage marker F4/80 antigen. In the lean condition, the alternative macrophage activation marker CD206 is expressed by feline and canine ATMs and arginase-1 by feline ATMs. Obesity is associated with interleukin-6 and interferon gamma expression and with overt tyrosine nitration in both feline and canine ATMs. This resembles the obesity-induced phenotype switch of murine and human ATMs. Thus, we show, for the first time, that the presence of ATMs is a general trait of mammals. The interaction between the adipose cells and SVF immune cells might be evolutionarily conserved among mammals.

The post-transcriptional control of gene expression is a complex and evolving field in adipocyte biology, with the premise that the delivery of microRNA (miRNA) species to the obese adipose tissue may facilitate weight loss. Cells shed extracellular vesicles (EVs) that may deliver miRNAs as intercellular messengers. However, we know little about the miRNA profile of EVs secreted by adipocytes during postnatal development. Here, we defined the miRNA cargo of EVs secreted by mouse adipocytes in two distinct phases of development: on postnatal day 6, when adipocytes are lipolytic and thermogenic, and on postnatal day 56, when adipocytes have active lipogenesis. EVs were collected from cell culture supernatants, and their miRNA profile was defined by small RNA sequencing. The most abundant miRNA of mouse adipocyte-derived EVs was mmu-miR-148a-3p. Adipocyte EVs on postnatal day 6 were hallmarked with mmu-miR-98-5p, and some miRNAs were specific to this developmental stage, such as mmu-miR-466i-5p and 12 novel miRNAs. Adipocytes on postnatal day 56 secreted mmu-miR-365-3p, and 16 miRNAs were specific to this developmental stage. The miRNA cargo of adipocyte EVs targeted gene networks of cell proliferation, insulin signaling, interferon response, thermogenesis, and lipogenesis. We provided here a database of miRNAs secreted by developing mouse adipocytes, which may be a tool for further studies on the regulation of gene networks that control mouse adipocyte development. [ABSTRACT FROM AUTHOR]

The present study sought to identify gene networks that are hallmarks of the developing inguinal subcutaneous adipose tissue (iWAT) and the interscapular brown adipose tissue (BAT) in the mouse. RNA profiling revealed that the iWAT of postnatal (P) day 6 mice expressed thermogenic and lipid catabolism transcripts, along with the abundance of transcripts associated with the beige adipogenesis program. This was an unexpected finding, as thermogenic BAT was believed to be the only site of nonshivering thermogenesis in the young mouse. However, the transcriptional landscape of BAT in P6 mice suggests that it is still undergoing differentiation and maturation, and that the iWAT temporally adopts thermogenic and lipolytic potential. Moreover, P6 iWAT and adult (P56) BAT were similar in their expression of immune gene networks, but P6 iWAT was unique in the abundant expression of antimicrobial proteins and virus entry factors, including a possible receptor for SARS-CoV-2. In summary, postnatal iWAT development is associated with a metabolic shift from thermogenesis and lipolysis towards fat storage. However, transcripts of beige-inducing signal pathways including β-adrenergic receptors and interleukin-4 signaling were underrepresented in young iWAT, suggesting that the signals for thermogenic fat differentiation may be different in early postnatal life and in adulthood. [ABSTRACT FROM AUTHOR]