Immunometabolic Crosstalk in Adipose Tissue Remodeling: Mechanisms and Therapeutic Perspectives

Abstract

Adipose tissue is a dynamic immunometabolic organ whose cellular heterogeneity and functional plasticity are central to systemic energy balance and metabolic regulation. Disruption of immune-adipocyte interactions is closely linked to the development of obesity and related metabolic disorders. In this review, we summarize current advances in understanding of the immune landscape in adipose tissue, with an emphasis on the distinct roles of immune cell subsets. Recent approaches including global and single-cell transcriptomic analysis, spatial profiling, and lineage tracing have expanded our ability to characterize these populations. We further highlight mechanisms through which immune cells influence adipocyte turnover, lipid handling, and thermogenesis, as well as reciprocal signals from adipocytes such as cytokines, lipid mediators, extracellular vesicles, and nutrient exchange. This bidirectional crosstalk governs adipose tissue remodeling and determines the occurrence of metabolic homeostasis or dysfunction. Finally, we provide perspectives into the ways in which these interactions may guide the identification of novel therapeutic targets for obesity and metabolic disease.

Keywords: Adipocytes; Adipose tissue; Inflammation; Macrophages; Obesity.

Figure 1

Lipid-associated macrophages in adipose tissue. (A) Schematic representation showing a monocyte—pre-lipid-associated macrophage (pre-LAM)—LAM trajectory. Pre-LAMs appear in early obesity with gene expression levels intermediate between those of monocytes and LAMs. Monocyte markers (e.g., C-X3-C motif chemokine receptor 1 [Cx3cr1], lymphocyte antigen 6C2 [Ly6c2]) decline along the trajectory, whereas LAM markers (e.g., galectin 3 [Lgals3], triggering receptor expressed on myeloid cells 2 [Trem2], and cathepsin L [Ctsl]) increase. In chronic obesity, LAMs diversify into adaptive states enriched for lysosomal/metabolic programs (e.g., peroxisome proliferator-activated receptor gamma [Pparg], lysosomal acid lipase [Lipa]) and maladaptive states enriched for inflammatory pathways (e.g., NLR family pyrin domain containing 3 [Nlrp3], toll-like receptor 2 [Tlr2], major histocompatibility complex [MHC] II, triggering receptor expressed on myeloid cells 1 [Trem1]), which increase in obesity and correlate with metabolic dysfunction. (B) Model of brown adipocyte-LAM interaction: Metabolically stressed brown adipocytes release lipidladen extracellular vesicles (EVs) containing damaged mitochondria. CD36⁺ LAMs capture these vesicles/debris and secrete transforming growth factor β1 (TGFβ1), which induces aldehyde dehydrogenase 1A1 (Aldh1a1) in neighboring brown adipocytes, compromising brown-adipocyte identity and promoting a shift toward a white adipocyte-like phenotype.

Figure 2

Transmembrane 4 L six family member 19 (TM4SF19)-driven regulation of lipid-associated macrophages in obese adipose tissue. (A) The lysosomal membrane protein TM4SF19 is upregulated in macrophages of visceral adipose tissue (VAT) and inhibits V0-V1 V-ATPase assembly, blunting lysosomal acidification in obesity. TM4SF19 promotes the emergence of pro-inflammatory lipid-associated macrophages (LAMs; triggering receptor expressed on myeloid cells 2 positive [TREM2⁺] CD11C⁺), which contribute to metabolic dysfunction in adipose tissue. In contrast, macrophage-specific TM4SF19 knockout (KO) promotes V-ATPase assembly and lysosomal acidification and increases the abundance of anti-inflammatory macrophages (lymphatic vessel endothelial hyaluronan receptor 1 positive [LYVE1⁺] CD206⁺) in VAT. (B) The schematic diagram illustrates a working model where LAMs can shift between adaptive and maladaptive phenotypes. In this model, TREM2 proteolysis and/or suppression of lysosomal programs may drive maladaptive features, whereas TM4SF19 deficiency might favor the adaptive state. Moreover, TM4SF19 KO or enhanced lysosomal acidification could promote a transition from TREM2⁺ LAMs toward LYVE1⁺ macrophages.

Figure 3

Regulation of group 2 innate lymphoid cell (ILC2) function in lean versus obese states. In the lean state, liver kinase B1 (LKB1) suppresses programmed cell death protein 1 (PD-1) expression in ILC2s and promotes mitochondrial activity by inhibiting mitophagy through upregulation of B-cell lymphoma-extra large (Bcl-xL) expression. ILC2s secrete type 2 cytokines, such as interleukin 5 (IL-5) and IL-13, to maintain metabolic homeostasis within adipose tissue. In addition, cannabinoid receptor 2 (CB2) agonists enhance ILC2 functionality through the activation of cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) signaling. In contrast, under obese conditions, LKB1 activity is diminished, while osteopontin (OPN) secreted by adipose tissue increases PD-1 expression. Interaction with PD-L1 expressed on adipocytes further augments PD-1 signaling in ILC2, leading to suppressed mitochondrial function, enhanced mitophagy, and induction of an exhausted ILC2 phenotype. AKT, AKT serine/threonine kinase; ERK, extracellular signal-regulated kinase; FABP5, fatty acid binding protein 5; FA, fatty acid; Pdcd1, programmed cell death 1; NFAT2, nuclear factor of activated T cells 2.

Figure 4

Prostaglandin E2 (PGE2)-mediated immunometabolic regulation in adipose tissue macrophages. Under lipolytic conditions, fatty acids are released from triglyceride (TG) hydrolysis and converted into arachidonic acid (AA) by cytosolic phospholipase A2 (cPLA2). AA is further metabolized to PGE2 via cyclooxygenases (COX1/2) in both adipocytes and macrophages. PGE2 engages prostaglandin E2 receptor 3 (EP3) and prostaglandin E2 receptor 4 (EP4) receptors, triggering distinct signaling pathways. EP3 coupling to Gαi suppresses adenylyl cyclase (AC), reducing cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) activity and limiting Sp1 transcription factor (SP1) phosphorylation. Lack of phosphorylated SP1 fails to induce DNA methyltransferases 1/3a (DNMT1/3a) expression, resulting in secreted protein acidic and cysteine rich (SPARC) promoter hypomethylation and sustained SPARC transcription, which influences adipogenesis through the Wnt/β-catenin pathway. Conversely, PGE2-EP4 signaling activates Gαs, stimulating AC and promoting an anti-inflammatory macrophage niche with enhanced recruitment. In cooperation with specialized pro-resolving mediators (SPMs) such as resolvins (RvDs) and maresins (MaRs), EP4 additionally engages Gi and phosphoinositide 3-kinase (PI3K) signaling, supporting a pro-phagocytic macrophage phenotype. β-AR, beta-adrenergic receptor; ATGL, adipose triglyceride lipase; HSL, hormone-sensitive lipase; MGL, monoacylglycerol lipase; FFA, free fatty acid.