Sexually dimorphic myeloid inflammatory and metabolic responses to diet-induced obesity

Abstract

Most murine studies are skewed toward the use of male mice to study obesity-induced metabolic dysfunction because of similar protection in female mice. We have investigated dietary obesity in a mouse model and have directly compared inflammatory responses in males and females. In this review we will summarize what is known about sex differences in diet-induced inflammation and will summarize our data on this topic. It is clear that sex differences in high-fat diet-induced inflammatory activation are due to cell intrinsic differences in hematopoietic responses to obesogenic cues, but further research is needed to understand what leads to sexually dimorphic responses. diabetes; high-fat diet; myelopoisis; obesity; sexual dimorphism GLOBAL OBESITY RATES have risen drastically in the past several decades with around one in every three individuals currently categorized as obese (34). The overall incidence of obesityrelated diseases such as diabetes and cardiovascular disease (CVD) also continues to rise as a result (3a). Obesity manifests as the result of an imbalance of caloric intake and energy expenditure. A major contributing factor to the increase in obesity rates is an increase in the consumption of calorie-dense foods rich in saturated fatty acids (4). With increased consumption of high-fat foods, individuals accrue body fat and thus have an elevated risk of developing obesity-related diseases. In this brief review we will emphasize the effects of diet-induced obesity, focusing primarily on sexually dimorphic responses of high-fat diet (HFD) priming of the immune system. An individual's response to HFD is dependent on several factors including sex, age, and ethnicity. What has become increasingly striking is that there is a clear sexual dimorphism in obesity and diabetes rates. While obesity rates are higher in women (34), men have higher rates of cardiovascular disease (CVD) and Type 2 diabetes (30, 36), suggesting that females are protected from the adverse effects of obesity (30). This is of particular importance because when investigating diabetes and CVD, many preclinical studies have been performed in males alone, leaving gaps in our knowledge of sexually dimorphic responses to obesity (45). Therefore, guidelines and therapies are being created based on investigations in males but are being implemented in men and women (13).It is important to investigate males and females to understand the contributing factors to these sex-specific differences. Previous studies have focused on altered hormone environments, anatomical fat distribution (17, 19), and energy expenditure differences. Women have been found to have 10% higher total body fat content compared with males of the same body mass index (BMI) (15). This dimorphism is especially profound in poor socioeconomic conditions, whereas richer environments show a smaller variance in adiposity between the sexes (11). This suggests that estrogen largely influences fat accumulation regardless of socioeconomic status (11). Additionally, when adiposity matched, fema...

Etiopathogenesis and Pharmacological Prevention of a Type-2 Diabetes Model in Male Mice

“…Several animal models of obesity described in the literature are somehow heterogeneous, since they exploit spontaneous mutations or diet-induced obesity in rodents; however, these latter models are often used to study polygenic causes of obesity and are believed by several investigators to better mimic the state of common obesity in humans, and may be the best choice for testing prospective therapeutics. These animal models may also show some of the most frequent comorbidities of obesity, such as hyperglycemia, insulin resistance, or diabetes-like syndromes (Lutz and Wood, 2012;Reyes, 2012;Habbout et al, 2013;Griffin et al, 2016;Heydemann, 2016); similar metabolic and immunologic alterations are observed in our model as well (Supplemental Material; Table 3). In synthesis, the three conditions (human type-2 diabetes, mouse high-fat diet/overfeeding syndrome, and our stress model of type-2 diabetes) share a number of similar alterations, as shown in Table 3, and we speculate that all three syndromes may also share some of the neuroendocrine pathogenetic mechanisms described in the present paper (Table 3).…”

Gender and Sex Differences in Adipose Tissue

“…Studies remain controversial about the gender differences in these ATMs and are limited by predominant sampling of subcutaneous adipose tissue in clinical sampling. Clinical studies implicate more ATMs in men and women with PCOS compared to premenopausal women [106•, 107]. …”

Arterial Calcification in Diabetes Mellitus

“…Male LDLR−/− mice also develop more severe hypertriglyceridemia 74 and hepatic steatosis when challenged with high fat diets 75 ; whether these differences 72–74 are responsible for gender-specific responses to atheroma modulation by PPAR-gamma agonists remains to be determined 74 . The enhanced myeloid adipo-inflammatory response of male mice to high fat diet feeding may be responsible, and these sexually dimorphic metabolic responses have been recently reviewed in detail 76 .…”