An unexpected finding

Visceral fat has long carried the reputation of being the primary driver of cardiometabolic risk. To test this assumption, researchers at Amsterdam University Medical Centers evaluated paired fat depots in patients with obesity, comparing those with and without dyslipidemia [1]. The findings challenged common expectations: transcriptomic alterations were most prominent in subcutaneous adipose tissue. Immune and inflammatory pathways accounted for a substantial portion of these shifts. What drives this heightened reactivity? Macrophages appear to hold the key, and their functional diversity was recently mapped in detail by researchers at Université Côte d'Azur in Nice, France [2].

Macrophages: orchestrating the immune milieu of fat

Adipose tissue is a bona fide immune organ populated by cells of both innate and adaptive immunity. Macrophages occupy center stage. In lean individuals, they represent approximately 10% of total adipose immune cells, but with expanding fat mass in obesity, this proportion surges to roughly 40% [3].

Calling them "orchestrators" is biologically apt. Macrophages sit squarely at the intersection of lipid storage, tissue turnover, and inflammatory signaling. They modulate lipolysis and lipid retention, guide adipogenesis, clear apoptotic adipocytes, and dictate whether the microenvironment leans pro- or anti-inflammatory. They also coordinate closely with adaptive immune cells: in human fat, pro-inflammatory macrophages cluster alongside B lymphocytes and mast cells—most visibly in crown-like structures (CLS)—whereas anti-inflammatory macrophages disperse throughout the tissue alongside natural killer cells [2].

Rodent models highlight just how essential macrophages are to adipose development. The survival and differentiation of most tissue-resident macrophages depend on colony-stimulating factor 1 (CSF1) signaling through its receptor CSF1R. Young rats lacking CSF1R, and consequently nearly devoid of macrophages, fail to form white adipose tissue altogether [2]. Macrophages also signal directly back to fat cells: in mouse adipose tissue, they produce PDGFcc, a growth factor indispensable for adipogenesis. Selectively abolishing PDGFcc in macrophages causes adipocytes to shrink, diverting unbuffered lipids into ectopic tissues [2].

Between tissue protection and inflammation

Adipose tissue macrophages are not a uniform population, but a specialized family of cells adapted to distinct microenvironments:

• Perivascular macrophages represent the majority: they express the LYVE1 marker and continuously sample and capture material from the bloodstream.
• Septal macrophages, localized near connective-tissue septa, express CD209b and regulate adipocyte progenitor fate. Experimental depletion of these cells triggers beige adipogenesis, shifting tissue toward thermogenesis.
• Perineural macrophages (CX3CR1+ MHC-IIhigh) closely line nerve fibers, where they internalize and degrade norepinephrine, thereby influencing local lipolysis.

In lean states, macrophages primarily maintain tissue homeostasis and defense:

• They control fatty acid efflux from adipocytes to prevent lipotoxicity.
• They scavenge apoptotic adipocytes.
• They secrete anti-inflammatory mediators such as IL-10.

With obesity, both total macrophage numbers and their subpopulation balance change. New cells accumulate through two distinct routes: recruitment of blood monocytes via the chemokine CCL2 and its receptor CCR2, or local proliferation of resident macrophages directly within adipose niches [2].

Which pathway dominates remains an active debate with conflicting findings. However, mouse studies demonstrate a clear link between macrophage recruitment and systemic metabolism. Adipose-specific overexpression of CCL2 increases tissue macrophages alongside circulating free fatty acids and hepatic triglycerides. Conversely, mice lacking CCR2 gain fewer adipose macrophages on high-fat diets and retain better glucose tolerance. Alongside cell accumulation, the phenotypic composition shifts: CD11c-positive pro-inflammatory subsets accumulate and secrete TNF-alpha, IL-1beta, and IL-6, fueling systemic insulin resistance [2].

Yet dividing macrophages into strictly "good" or "bad" categories oversimplifies their biology. This complexity is best illustrated by lipid-associated macrophages (LAMs), specialized cells equipped to handle heavy lipid loads:

• Identity. LAMs upregulate genes governing lipid uptake, transport, and catabolism, distinguished by markers including the TREM2 receptor and CD36. They can differentiate from both resident tissue macrophages and recruited monocytes [2].
• Accumulation. Virtually absent in lean adipose tissue, LAMs expand sharply during obesity as adipocytes become overloaded with lipids [2].
• Protective role. LAMs actively buffer excess lipids. On a high-fat diet, Trem2-deficient mice develop hypertrophic, dying adipocytes and intensified adipose inflammation, demonstrating that LAMs shield tissue from lipotoxic collapse [2].
• Pathogenic flip side. Deleting the LAM-associated protein TM4SF19 reduces macrophage accumulation and improves metabolic parameters [2]. A similar duality characterizes metabolically activated macrophages (MMe) found in humans and mice: they secrete pro-inflammatory IL-1beta while simultaneously scavenging dead adipocytes to curb ectopic fat storage—two divergent tasks regulated by the same enzyme, NADPH oxidase 2 [2].

Divergence between subcutaneous and visceral depots

Tissue health reflects not just overall macrophage density, but the relative balance of their functional subsets. Subcutaneous and visceral depots differ substantially in this regard: patients with obesity show higher expressions of LAM markers in subcutaneous fat than in visceral compartments [4]. This observation aligns with clinical findings from Zwartjes et al., who reported that subcutaneous fat showed the strongest molecular responsiveness to dyslipidemia [1]. A direct causal link between these two observations has yet to be established.

Crucially, much of our understanding of macrophage subsets stems from murine models. In humans, all adipose tissue macrophages express HLA-DR, meaning mouse markers cannot be applied interchangeably. The human phenotypes of certain subsets—such as nerve-associated macrophages—remain to be fully characterized [2].

Clinical findings in humans

The cross-sectional study examined 125 patients with obesity from the BARIA cohort scheduled for bariatric surgery. The cohort had a mean body mass index (BMI) of 39.5 kg/m² and was 80.8% female. Researchers contrasted patients with dyslipidemia against those with normal lipid profiles [1].

Cohort Characteristics:

• Dyslipidemia was present in 43 patients (34.4%)
• Mean BMI did not differ significantly between groups
• Patients with dyslipidemia had lower high-density lipoprotein cholesterol (HDL-C; 1.02 vs. 1.35 mmol/L) and lower apolipoprotein AI
• Triglycerides were higher (1.62 vs. 1.24 mmol/L), alongside elevated apolipoprotein B.

Tissue transcriptomics

RNA sequencing of paired subcutaneous and visceral adipose biopsies revealed alterations across pathways governing inflammation, oxidative stress, and adipogenesis. The most pronounced molecular shifts emerged within subcutaneous adipose tissue [1].

Key regional differences

• In subcutaneous fat, dyslipidemia was associated with higher expression of the pro-inflammatory gene IL32 and downregulation of NFIL3. NFIL3 is an immunometabolic regulator that, in the cited literature, promotes an anti-inflammatory milieu by supporting M2 macrophage polarization and regulatory T cells.
• In visceral fat, expression of the chemokine CCL3, known to recruit monocytes and macrophages, correlated positively with circulating triglyceride levels.

The authors assessed bulk tissue transcriptomics rather than single-cell profiles. Consequently, these findings highlight meaningful associations between dyslipidemia and adipose remodeling, but they do not prove that macrophages initiated these changes or caused the lipid abnormalities [1].

Relevance for aesthetic and body-contouring practice

Subcutaneous fat is the primary target of non-invasive body contouring technologies, including cryolipolysis, radiofrequency devices, and injectable lipolytics. These findings underscore that subcutaneous tissue is an immunologically dynamic, metabolically responsive organ rather than an inert cosmetic cushion [1, 2]. Variations in macrophage subsets and the baseline balance between protective and pro-inflammatory signaling may help explain why individual clinical responses to identical body-contouring protocols can vary, even though this question was not directly examined in the study.

Caution is essential when translating these observations to aesthetic practice. The study evaluated patients with severe obesity awaiting bariatric surgery and did not assess how aesthetic procedures affect macrophage dynamics. Translating these findings into direct clinical recommendations would be premature. The marked sensitivity of subcutaneous fat to systemic metabolic cues offers a compelling hypothesis and a valuable direction for future aesthetic research, rather than a definitive guide for clinical decision-making [1, 2].

References

1. Zwartjes M.S.Z., de Jonge P.A., van de Laar A.W. et al. Adipose tissue inflammation, oxidative stress, and altered adipogenesis are associated with dyslipidemia in obesity: a multiomics profiling study. J Am Heart Assoc 2026; 15: e047397.
2. Grenet S., Ivanov S., Chinetti G. Adipose-tissue macrophage diversity and functions. Int J Mol Sci 2026; 27(4): 1759.
3. Weisberg S.P., McCann D., Desai M., et al. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003; 112(12): 1796–1808.
4. Reyes-Farias M., Fernández-García P., Corrales P. et al. Lipid-associated macrophages are more abundant in subcutaneous than visceral adipose tissue in patients with obesity. Obesity. 2025; 33(8): 1543–1554.