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Abstract
Simple SummaryObesity is a global health concern with numerous associated comorbidities. This study aims to provide a qualitative assessment of changes that may occur in tissues, organs, and plasma during the early stages of obesity development and how it may differ between male and female using a mouse model of diet induced obesity. Notable changes, not previously reported, were observed in the lungs, liver, kidney, spleen, and heart, which may suggest early signs of developing an obesity associated comorbidity. Leptin levels with notable sexual dimorphisms changes significantly in early obesity and was observed to also correlate with insulin levels. Interestingly, males and females showed different inflammatory cytokine profiles with females exhibiting a more anti-inflammatory cytokine profile, notably the IL-6/IL-10 axis of cytokine regulation may account for their significantly lower weight gain compared to males. Thus, this study provides valuable information which may aid in understanding the development of some obesity associated diseases at the early stages and could assist in developing effective intervention strategies in males and females.Despite obesity being a major health concern, information on the early clinical changes that occur in plasma and tissues during obesity development and the influence of sexual dimorphism is lacking. This study investigated changes in tissue and organ histology, macrophage infiltration, plasma hormones, lipid, and chemokine and cytokine levels in mice fed on a high fat diet for 11-weeks. An increase in adiposity, accompanied by adipocyte hypertrophy and macrophage infiltration, was observed to be significantly greater in males than females. Important changes in cell morphology and histology were noted in the lungs, liver, kidney, spleen, and heart, which may indicate early signs for developing obesity associated comorbidities. Leptin, but not adiponectin, was significantly altered during weight gain. Additionally, leptin, but not adiposity, correlated with insulin levels. Interestingly, GM-CSF, TNFα, and IL-12 (p70) were not produced in the early stages of obesity development. Meanwhile, the production of MCP-1, IP-10, RANTES, IL-10, IL-6, KC, and IL-9 were greatly influenced by sexual dimorphism. Importantly, IL-6/IL-10 axis of anti-inflammatory cytokine regulation was observed only in females and may account for their significantly lower weight gain compared to males. This study provides new knowledge on how sexual dimorphism may influence the development of obesity and associated comorbidities.
Highlights
Obesity is characterized by the accumulation of excess body fat or adiposity due to adipocyte hyperplasia or hypertrophy
Over the 11-week period, mice on high fat diet (HFD) gained significantly more weight (p < 0.0001) compared to those on CD starting from week 3 (Figure 1A) and this was observed in both sexes (Females: p = 0.0004; Males: p < 0.0001) (Figure 1B)
Average weekly food intake was similar in males and females on either CD or HFD; the caloric intake was significantly higher in the HFD animals (Supplementary Table S1)
Summary
Obesity is characterized by the accumulation of excess body fat or adiposity due to adipocyte hyperplasia (increase in number) or hypertrophy (increase in size). Adipose tissue expansion through adipocyte hypertrophy leads to a dysfunctional adipose tissue commonly found in obese individuals [4], which results to adipokine production, adipocyte insulin resistance, macrophage infiltration, and production of pro-inflammatory factors, as well as release of free-fatty acids (FFA) [5]. Adipose tissue hypoxia and the release of FFA that occur during adipose tissue expansion may initiate the recruitment of macrophages. These macrophages are of the M1 phenotype and secrete pro-inflammatory cytokines and chemokines, which further recruits more macrophages and other immune cells into the adipose tissue [6,7]. Obesity is associated with a low-grade chronic inflammation characterized by an increase in proinflammatory cytokines (IL-6, TNF-α, IL-1α) and a reduction in anti-inflammatory cytokines (IL-4, IL-10, and IL-13) [8]
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