Sex-based differences in phagocyte metabolic profile in rats with monosodium glutamate-induced obesity

Abstract

The important component of obesity pathogenesis is inflammatory activation of innate immune cells within adipose tissue and in other body locations. Both the course of obesity and innate immune reactivity are characterized by sex-associated differences. The aim of the work was a comparative investigation of metabolic profiles of phagocytes from different locations in male and female rats with MSG-induced obesity. The administration of monosodium glutamate (MSG) caused obesity, with sex-associated differences, that was more severe in male rats. Obesity was associated with pro-inflammatory activation of CD14+ phagocytes from adipose tissue in female, but not in male rats, which was demonstrated by decreased phagocytosis activity along with increased ROS generation. Phagocytes from the peritoneal cavity and peripheral blood of obese female rats exhibited neutral metabolic profile, whereas those cells from obese male rats displayed a pro-inflammatory metabolic profile. Thus, the manifestation of obesity-induced inflammation was characterized by different patterns of metabolic profile of phagocytes in male and female rats. Identified immune cell characteristics expand our knowledge of obesity immunobiology and may help to develop more effective preventive and therapeutic interventions for obese patients of different sexes.

Introduction

The worldwide prevalence of obesity and its metabolic complications have substantially increased in recent years1,2. The propensity towards development of obesity differs between the sexes, and this is, first of all, due to the effect of sex hormones on adipocyte metabolism3,4. In addition, sex-associated differences in cell types, other than adipocytes within adipose tissue, such as innate immune cells, also account for differences in obesity between males and females. Sex-based differences in immune responses are well documented. These differences are attributed to the immunomodulatory effects of sex hormones, as well as being related to the X chromosome gene contributions. The X chromosome encodes for a number of critical genes involved in the regulation of immunity, such as Toll-like receptors. Moreover, the X chromosome contains about 10% of all microRNAs in the genome, which regulate immune cell differentiation and functioning5,6. The sex differential expression of PRRs stipulates sex-specific activity of the innate immune cells following stimulation. Peritoneal phagocytes from female rodents produce higher levels of anti-inflammatory prostanoids, than do male-derived cells in response to microbial stimuli. Whereas, male phagocytes produce more pro-inflammatory cytokines and chemokines following PRR stimulation, than do female cells. The phagocytic activity of innate immune cells from many locations is higher in females than in males7,8,9. Sex hormones exert different immunomodulating effects. Natural level of testosterone shows a significant positive relationship with Th1 immune response, whereas natural level of estrogen – with Th2 immune cell metabolic shift10,11.

Adipose tissue and immune system are closely interrelated. Major alterations of immune responses expressed during obesity, have been represented as obesity-induced low-grade inflammation or «meta-inflammation»12,13. This disorder is associated with an increase in local adipose tissue of inflammatory cytokines and other proteins (TNFα, IL-1b, IL-6, IFNγ, MCP-1, iNOS) secretion, innate immune cell activation (adipose tissue infiltration by pro-inflammatory macrophages and neutrophils) as well as activation of pathogenic adaptive immune response14,15. The leading role in obesity-induced inflammation has been conferred on adipose tissue resident macrophages, as major inflammatory effector cells, whose number is increased in the fat, and producers of molecules that contributed to the inflammation. More recent studies have shown that adipose tissue resident macrophages express pro-inflammatory M1 (classically activated) phenotype during obesity, and they are closely related to the development of obesity-induced insulin resistance. In contrast, the fat from lean individuals contains mainly anti-inflammatory M2 (alternatively activated) macrophages, whose essential functions are debris phagocytosis and reparation, following the resolution of the inflammatory process16,17,18,19. An important role in obesity-induced inflammation is played by neutrophils as adipose tissue infiltrating cells and macrophage activators20,21. Although it is well established that obesity is associated with alterations of local (in adipose tissue) phagocyte metabolic profile, little is known about obesity-associated changes in phagocytes from other locations, which are involved in systemic meta-inflammation. Some authors have hypothesized that sex-associated differences in phagocyte metabolic polarization could play a role in the different disease incidence between males and females. Studies suggest that strategies to develop therapeutic interventions to treat obesity-associated diseases must take into account the differences in immune responses between males and females22,23.

Monosodium glutamate (MSG), which is known in the food industry as an umami taste substance, has been used for decades, not only in studies of diet-induced obesity, but also as a primary factor to induce obesity in animal models24,25,26,27. MSG administration in newborn animals causes injury to the ventromedial hypothalamic and arcuate nuclei. This leads to the development of obesity due to the lack of controlled balance between energy absorption and expenditure. Detailed mechanisms of this process have not been clearly understood25. A study on mice27 has shown sex- and strain-associated variations of metabolic and hormonal status during MSG-induced obesity.

In the present study, we performed a comparative investigation of metabolic profiles of phagocytes from different locations in male and female rats with MSG-induced obesity. We demonstrated that MSG-induced obesity development in rats is associated with the sex-dependent changes in the metabolic state, and the functional activity of monocytes and granulocytes located in adipose tissue, peritoneal cavity and peripheral circulation.

Results

White adipose tissue (WAT) measures in male and female rats with MSG-induced obesity

Neonatal treatment with MSG resulted in the onset of obesity in rats at the age of 4 months, and this was associated with hyperleptinemia and hyperinsulinemia, as described earlier28. The development of obesity was associated with slight diminution of animal body weight in male rats. Lee indices were also slightly increased only in male MSG-treated animals (Table 1). The administration of MSG during the neonatal period led to a significant gain of WAT depot weight in male and female rats (Table 1). Nevertheless, the total weight of WAT in obese male rats amounted to a quarter of animal body weight, whereas, in female rats, the relative weight of the total WAT was 10% of body weight. Sex-based differences in the distribution of WAT depots were also observed. The onset of obesity in female rats was characterized by a 2.5 fold increase of visceral fat pad weight, and the appearance of subcutaneous fat pads. No changes were registered in perigonadal WAT depots. In male rats injected with MSG, two-fold and 1.5 fold increase of visceral and perigonadal adipose tissue depots, correspondingly, was found, and the generation of large subcutaneous fat pads were registered (Table 1).

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