Sex Differences in Macrophage Responses to Obesity-Mediated Changes Determine Migratory and Inflammatory Traits

Abstract

The mechanisms whereby obesity differentially affects males and females are unclear. Because macrophages are functionally the most important cells in obesity-induced inflammation, we sought to determine reasons for male-specific propensity in macrophage migration. We previously determined that male mice fed a high-fat diet exhibit macrophage infiltration into the hypothalamus, whereas females were protected irrespective of ovarian estrogen, in this study, we show that males accumulate more macrophages in adipose tissues that are also more inflammatory. Using bone marrow cells or macrophages differentiated in vitro from male and female mice fed control or high-fat diet, we demonstrated that macrophages derived from male mice are intrinsically more migratory. We determined that males have higher levels of leptin in serum and adipose tissue. Serum CCL2 levels, however, are the same in males and females, although they are increased in obese mice compared with lean mice of both sexes. Leptin receptor and free fatty acid (FFA) receptor, GPR120, are upregulated only in macrophages derived from male mice when cultured in the presence of FFA to mimic hyperlipidemia of obesity. Unless previously stimulated with LPS, CCL2 did not cause migration of macrophages. Leptin, however, elicited migration of macrophages from both sexes. Macrophages from male mice maintained migratory capacity when cultured with FFA, whereas female macrophages failed to migrate. Therefore, both hyperlipidemia and hyperleptinemia contribute to male macrophage-specific migration because increased FFA induce leptin receptors, whereas higher leptin causes migration. Our results may explain sex differences in obesity-mediated disorders caused by macrophage infiltration.

Monocyte Trafficking and Polarization Contribute to Sex Differences in Meta-Inflammation

“…Our migration studies with monocytes are consistent with others showing male monocyte-derived macrophages to migrate readily to fatty acid exposure whereas female macrophages have dampened migration ( 39 ). While the literature is controversial about the importance of MCP1 in obesity-induced inflammation ( 47 , 48 ), using the chemokine and PA treatment, we identified that male monocytes specifically have a more robust trafficking response in vitro.…”

“…Chemokines and their receptors are noted to have significant redundancy ( 38 ), but an understanding of differences by sex with diet is helpful for understanding the dimorphism ( 39 ). Among the top differentially expressed genes in pathways associated with cell adhesion, migration, and interaction, we looked at markers for pro-inflammatory states of ATMs in heatmaps.…”

The Obese Brain: Mechanisms of Systemic and Local Inflammation, and Interventions to Reverse the Cognitive Deficit

“…The decrease in estrogen levels in menopausal women is associated with the loss of subcutaneous fat and the abdominal fat accumulation ( Lizcano and Guzmán, 2014 ). In support of estrogen importance, increased adiposity after oophorectomy and ovarian estrogen clearance were observed in rodents and monkeys ( Chen et al, 2021 ). In the case of men, low testosterone levels have also been proposed as a risk factor for pathophysiology, including insulin sensitivity and DM2 ( Terrazas et al, 2019 ).…”

“…There is a differential response in adiposity and the prevalence of obesity-associated diseases between males and females, particularly in mammals. In obese men, the occurrence of heart disease and myocardial infarction is higher, while in women, obesity is associated with ischemic stroke ( Chen et al, 2021 ). When comparing men and women with the same BMI, it has been observed that women have a 10% higher body fat content.…”

Adipokines as Immune Cell Modulators in Multiple Sclerosis

“…Furthermore, gender-specific associations of gene polymorphisms with disease susceptibility have been found in MS patients [ 44 ]. In addition, cellular responses to adipokines might differ between gender, since more and more cell types are being discovered of which their function and phenotype is dictated by gender [ 120 , 121 , 122 ].…”