Immune cell-derived adipokines : role in white adipose tissue function and link to metabolic health

The white adipose tissue (WAT) is home to a vast array of immune cells that control local homeostasis and metabolism by engaging in intricate crosstalk with adipocytes and their precursors through secreted factors (adipokines). In the obese WAT, these immune cells adopt a pro-inflammatory profile, resulting in a state of chronic low-grade inflammation that can perturb local and systemic metabolic function. This thesis aimed to study physiological and pathological aspects of the interplay between immune cellderived adipokines and processes pertaining to the expansion and metabolic function of the WAT.

A postprandial induction of the pro-inflammatory cytokine interleukin (IL)-1b was previously demonstrated in macrophages of the WAT, but not other tissues, hinting to a possible involvement in local energy handling. Therefore, in study I, we employed in vivo and in vitro models to investigate a physiological, metabolic role of IL-1b in the WAT. To our surprise, IL-1 signaling was of minor importance in mature adipocytes. Instead, we identified adipocyte precursors as the major target of IL-1b in the WAT, where it stimulated the formation of new fat cells, a process linked to preserved metabolic health during obesity development. Strikingly distinct effects caused by acute and chronic treatments led us to propose that postprandial surges in IL-1b has a physiological role in promoting healthy WAT expansion but that this effect may be lost in the chronically inflamed obese WAT.

Study II set out to identify WAT-secreted factors involved in cardiometabolic diseases of non-obese individuals. An adipokine screen identified the chemokine CCL18 as significantly elevated in cardiometabolic disease groups compared to healthy controls (all non-obese). Further explorations led us to conclude that CCL18 recruits CD4+ T cells and activates them to secrete interferon g and transforming growth factor b1, which in turn stimulate lipolysis of adipocytes, thereby contributing to cardiometabolic disease through release of fatty acids into circulation.

Women generally display a healthier metabolic phenotype than men. Whether differences in WAT inflammatory status may account for this is unknown. The antiinflammatory cytokine IL-10 was previously shown to be elevated in WAT of obese women. Study III explored possible sex differences in WAT production of this cytokine. IL-10 secretion and IL-10-producing macrophages were elevated in WAT of obese women, but not men, with type 2 diabetes. Estrogens had no direct effect on IL-10 expression in vitro. This reveals a sex-specific regulation of IL-10 production in obesity, which may provide women with relative protection from obesity-associated inflammation.

Overall, this thesis has provided new insights on the complex role of immune cellderived adipokines in metabolism and expansion of the WAT under different contexts, and how this may be linked to metabolic health.

List of scientific papers

I. IL-1b promotes adipogenesis by directly targeting adipocyte precursors. Hofwimmer K*, de Paula Souza J*, Subramanian N, Rachid L, Méreau H, Zhao C, Vujičić M, Wernstedt Asterholm I, Böni-Schnetzler M, Meier DT2, Donath MY#, Laurencikiene J#. *Shared first authors; #Shared last authors. [Manuscript]

II. Adipose tissue specific CCL18 associates with cardiometabolic diseases in non-obese individuals implicating CD4+ T cells. Subramanian N, Hofwimmer K, Tavira B, Massier L, Andersson DP, Arner P, Laurencikiene J. Cardiovasc Diabetol. 2023 Apr 12;22(1):84.
https://doi.org/10.1186/s12933-023-01803-w

III. Sex-specific regulation of IL-10 production in human adipose tissue in obesity. Subramanian N, Tavira B, Hofwimmer K, Gutsmann B, Massier L, Abildgaard J, Juul A, Rydén M, Arner P, Laurencikiene J. Front Endocrinol (Lausanne). 2022 Oct 13:13:996954.
https://doi.org/10.3389/fendo.2022.996954