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IntroductionObesity is associated with a plethora of health complications, including increased susceptibility to infections or decreased vaccine efficacy, partly due to dysregulated immune responses. Monocytes play a crucial role in innate immunity, yet their functional alterations in obesity remain poorly understood.MethodsHere, we employed proteomic and metabolomic analyses to investigate monocyte characteristics in individuals with overweight, obesity, impaired glucose tolerance (IGT), and type 2 diabetes (T2D), compared to lean donors.Results and discussionOur results revealed distinct molecular signatures in monocytes from individuals with obesity, with significant alterations in pathways related to metabolism, cellular migration, and phagocytosis. Moreover, LPS-induced activation of monocytes unveiled heightened metabolic reprogramming towards glycolysis in subjects with obesity accompanied by dysregulated cytokine responses and elevated oxidative stress. Additionally, monocytes from donors with obesity exhibited increased lipid droplet accumulation. These findings shed light on the immunometabolic dysregulation underlying obesity-associated immune dysfunction, highlighting potential targets for therapeutic intervention.

Circulating monocytes can be divided into classical (CM), intermediate (IM), and non-classical monocytes (NCM), and the classical monocytes also contain CD56+ monocytes and monocytic myeloid-derived suppressor cells (M-MDSC). The aim of the study was to evaluate the occurrence of the monocyte subpopulations in human obesity. Twenty-seven normal, 23 overweight, and 60 obese individuals (including 17 obese individuals with normal glucose tolerance and 27 with type 2 diabetes) were included into this study. Peripheral blood mononuclear cells were isolated from human blood, and surface markers to identify monocyte subpopulations were analyzed by flow cytometry. Obese individuals had higher numbers of total monocytes, CM, IM, CD56+ monocytes, and M-MDSCs. The number of CM, IM, CD56+ monocytes, and M-MDSCs, correlated positively with body mass index, body fat, waist circumference, triglycerides, C-reactive protein, and HbA1c, and negatively with high-density lipoprotein cholesterol. Individuals with obesity and type 2 diabetes had higher numbers of IM, NCM, and M-MDSCs, whereas those with obesity and impaired glucose tolerance had higher numbers of CD56+ monocytes. In summary, the comprehensive analysis of blood monocytes in human obesity revealed a shift of the monocyte compartment toward pro-inflammatory monocytes which might contribute to the development of low-grade inflammation in obesity, and immune-suppressive monocytes which might contribute to the development of cancer in obesity.

Monocytes enter sites of microbial or sterile inflammation as the first line of defense of the immune system and initiate pro-inflammatory effector mechanisms. We show that activation with bacterial lipopolysaccharide (LPS) induces them to undergo a metabolic shift toward aerobic glycolysis, similar to the Warburg effect observed in cancer cells. At sites of inflammation, however, glucose concentrations are often drastically decreased, which prompted us to study monocyte function under conditions of glucose deprivation and abrogated Warburg effect. Experiments using the Seahorse Extracellular Flux Analyzer revealed that limited glucose supply shifts monocyte metabolism toward oxidative phosphorylation, fueled largely by fatty acid oxidation at the expense of lipid droplets. While this metabolic state appears to provide sufficient energy to sustain functional properties like cytokine secretion, migration, and phagocytosis, it cannot prevent a rise in the AMP/ATP ratio and a decreased respiratory burst. The molecular trigger mediating the metabolic shift and the functional consequences is activation of AMP-activated protein kinase (AMPK). Taken together, our results indicate that monocytes are sufficiently metabolically flexible to perform pro-inflammatory functions at sites of inflammation despite glucose deprivation and inhibition of the LPS-induced Warburg effect. AMPK seems to play a pivotal role in orchestrating these processes during glucose deprivation in monocytes.