No abstract

Obesity-induced chronic inflammation is associated with metabolic disease. Results from mouse models utilizing a high-fat diet (HFD) have indicated that an increase in activated macrophages, including CD11c adipose tissue macrophages (ATMs), contributes to insulin resistance. Obesity primes myeloid cell production from hematopoietic stem cells (HSCs) and Toll-like receptor 4 (TLR4), and the downstream TIR domain-containing adapter protein-inducing interferon-β (TRIF)- and MyD88-mediated pathways regulate production of similar myeloid cells after lipopolysaccharide stimulation. However, the role of these pathways in HFD-induced myelopoiesis is unknown. We hypothesized that saturated fatty acids and HFD alter myelopoiesis by activating TLR4 pathways in HSCs, differentially producing pro-inflammatory CD11c myeloid cells that contribute to obesity-induced metabolic disease. Results from reciprocal bone marrow transplants (BMTs) with and WT mice indicated that TLR4 is required for HFD-induced myelopoiesis and production of CD11c ATMs. Experiments with homozygous knockouts of (encoding a suppressor of MyD88 inactivation) and in competitive BMTs revealed that MyD88 is required for HFD expansion of granulocyte macrophage progenitors and that is required for pregranulocyte macrophage progenitor expansion. A comparison of WT,, , and mice on HFD demonstrated that TLR4 plays a role in the production of CD11c ATMs, and both and mice produced fewer ATMs than WT mice. Moreover, HFD-induced TLR4 activation inhibited macrophage proliferation, leading to greater accumulation of recruited CD11c ATMs. Our results indicate that HFD potentiates TLR4 and both its MyD88- and TRIF-mediated downstream pathways within progenitors and adipose tissue and leads to macrophage polarization.

Background Weight loss by surgery or lifestyle changes is strongly recommended for obese individuals to improve metabolic health, but the underlying impairments that persist from a history of obesity remain unclear. Recent investigations demonstrate a persistent inflammatory state with weight loss and bariatric surgery, but the mechanism and impact are not fully understood. Additionally, these studies have not been performed in females although women are the majority of individuals undergoing weight loss interventions. Methods The goal of this study was to determine the sex differences in metabolically induced inflammation after dietary weight loss (WL) or bariatric surgery. Following a 60% high-fat diet (HFD) for 12 weeks, C57Bl/6j mice underwent either a dietary switch to normal chow for WL or vertical sleeve gastrectomy (VSG) and were evaluated 8 weeks after intervention. WL effects on myelopoiesis were further evaluated with bone marrow chimeras. Results Both sexes had a decrease in adiposity and total weight following WL or VSG intervention. With HFD, females had very little inflammation and no further increase with WL, but males had persistent inflammation even after WL despite metabolic improvement. Interestingly, after VSG, myeloid inflammation was increased in the livers of males and to a lesser extent in females. Conclusions These studies demonstrate that regardless of sex, it is critical to assess an individuals’ history of obesity rather than just rely on current weight status in medical decision-making. There are long-lasting effects on tissue inflammation in both sexes especially with surgical weight loss. Dietary change is overall most effective to improve meta-inflammation in obese males on its own or in combination with surgical weight loss.

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...

Aging, like obesity, is associated with metabolic and inflammatory alterations within adipose tissue in older individuals. Younger females are protected from adipose inflammation, but older post-menopausal females exhibit exaggerated visceral adiposity correlated with increased disease risk. Obesity accelerates the onset and progression of age-associated diseases, but it is unclear if aging and obesity drive adipose tissue dysfunction in a sexually dimorphic fashion. We investigated adipose tissue metabolism and inflammation in a diet-induced obesity model in young and old mice. We identified age related sex differences in adipose tissue macrophages (ATMs), fibrosis and lipid metabolism in male and female visceral fat depot (GWAT). Although aging normalized body weights between the sexes, females remained protected from proinflammatory ATMs and stimulated lipolysis failed to adversely affect the inflammatory state even with obesity. Older obese males had augmented CD11c + ATMs and higher insulin levels, while females showed increased visceral adiposity and exaggerated Pparγ, and Pgc1α expression. Obesity in aging demonstrated similar expression of GWAT p53, p16, p21, Timp1 and Tgfβ1 in both sexes. Our studies suggest that even with aging, female GWAT shows an attenuated inflammatory response compared to males due to an efficient oxidative metabolism combined with an active tissue remodeling state.

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