Excessive increased adipose tissue mass in obesity is associated with numerous co-morbid disorders including increased risk of type 2 diabetes, fatty liver disease, hypertension, dyslipidemia, cardiovascular diseases, dementia, airway disease and some cancers. The causal mechanisms explaining these associations are not fully understood. Adipose tissue is an active endocrine organ that secretes many adipokines, cytokines and releases metabolites. These biomolecules referred to as adipocytokines play a significant role in the regulation of whole-body energy homeostasis and metabolism by influencing and altering target tissues function. Understanding the mechanisms of adipocytokine actions represents a hot topic in obesity research. Among several secreted bioactive signalling molecules from adipose tissue and liver, retinol-binding protein 4 (RBP4) has been associated with systemic insulin resistance, dyslipidemia, type 2 diabetes and other metabolic diseases. Here, we aim to review and discuss the current knowledge on RBP4 with a focus on its role in the pathogenesis of obesity comorbid diseases.

Lipedema may be considered a model for healthy expandability of subcutaneous adipose tissue (SAT). This condition is characterized by the disproportional and symmetrical SAT accumulation in the lower-body parts and extremities, avoiding the abdominal area. There are no circulating biomarkers facilitating the diagnosis of lipedema. We tested the hypothesis that women living with lipedema present a distinct pattern of circulating parameters compared to age- and BMI-matched women. In 26 women (Age 48.3 ± 13.9 years, BMI 32.6 ± 5.8 kg/m2; lipedema group: n=13; control group: n=13), we assessed circulating parameters of glucose and lipid metabolism, inflammation, oxidative stress, sex hormones and a proteomics panel. We find that women with lipedema have better glucose metabolism regulation represented by lower HbA1c (5.55 ± 0.62%) compared to controls (6.73 ± 0.85%; p<0.001); and higher adiponectin levels (lipedema: 4.69 ± 1.99 mmol/l; control: 3.28 ± 1.00 mmol/l; p=0.038). Despite normal glycemic parameters, women with lipedema have significantly higher levels of total cholesterol (5.84 ± 0.70 mmol/L vs 4.55 ± 0.77 mmol/L in control; p<0.001), LDL-C (3.38 ± 0.68 mmol/L vs 2.38 ± 0.66 mmol/L in control; p=0.002), as well as higher circulating inflammation (top 6 based on p-values: TNFSF14, CASP8, EN-RAGE, EIF4EBP1, ADA, MCP-1) and oxidative stress markers (malondialdehyde, superoxide dismutase and catalase). Our findings suggest that the expected association between activation of inflammatory and oxidative stress pathways and impaired glucose metabolism are counterbalanced by protective factors in lipedema.

Adipose tissue (AT) storage capacity is central in the maintenance of whole-body homeostasis, especially in obesity states. However, sustained nutrients overflow may dysregulate this function resulting in adipocytes hypertrophy, AT hypoxia, inflammation and oxidative stress. Systemic inflammation may also contribute to the disruption of AT redox equilibrium. AT and systemic oxidative stress have been involved in the development of obesity-associated insulin resistance (IR) and type 2 diabetes (T2D) through several mechanisms. Interestingly, fat accumulation, body fat distribution and the degree of how adiposity translates into cardio-metabolic diseases differ between ethnicities. Populations of African ancestry have a higher prevalence of obesity and higher T2D risk than populations of European ancestry, mainly driven by higher rates among African women. Considering the reported ethnic-specific differences in AT distribution and function and higher levels of systemic oxidative stress markers, oxidative stress is a potential contributor to the higher susceptibility for metabolic diseases in African women. This review summarizes existing evidence supporting this hypothesis while acknowledging a lack of data on AT oxidative stress in relation to IR in Africans, and the potential influence of other ethnicity-related modulators (e.g., genetic-environment interplay, socioeconomic factors) for consideration in future studies with different ethnicities.