Differences in Hematopoietic Stem Cells Contribute to Sexually Dimorphic Inflammatory Responses to High Fat Diet-induced Obesity

Singer, Kanakadurga; Maley, Nidhi; Mergian, Taleen; DelProposto, Jennifer B.; Cho, Kae Won; Zamarron, Brian F.; Martinez-Santibañez, Gabriel; Geletka, Lynn M.; Muir, Lindsey A.; Wachowiak, Phillip; Demirjian, Chaghig; Lumeng, Carey N.

doi:10.1074/jbc.m114.634568

Cited by 93 publications

(132 citation statements)

References 43 publications

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“…We found that while females had normal myeloid progenitors at baseline, these cells did not expand with HFD as we saw in males. Examining the bone marrow ex vivo, we found that female BM produced less granulocyte and macrophage colonies than males after palmitic acid (saturated fatty acid) stimulation and produced lower cytokine responses to lipopolysaccharides (LPS) (47). Fig.…”

Section: Sexually Dimorphic Macrophage Responses To High-fat Dietmentioning

confidence: 99%

“…This suggests that there is a cell-intrinsic difference in hematopoietic responses to obesity between the sexes. It may also indicate that there is a permanent, lifelong change within the HSC progenitor population after exposure to a HFD (47).…”

Section: Sexually Dimorphic Macrophage Responses To High-fat Dietmentioning

confidence: 99%

“…To understand the different inflammatory responses to HFD, we looked at ATMs and HSC/bone marrow (BM) populations in male and female animals on HFD (47). Using a 60% lard-based HFD chow, both males and females were able to gain weight and adiposity, though males gained more body weight compared with females.…”

Section: Sexually Dimorphic Macrophage Responses To High-fat Dietmentioning

confidence: 99%

“…Females also exhibited an expansion of macrophages but primarily of the CD11c Ϫ type. To understand the inflammatory environment created in the adipose tissue, we looked at the adipose tissue gene expression of inflammatory cytokines and saw that expression was reduced in females on HFD compared with males on HFD (47).…”

Section: Sexually Dimorphic Macrophage Responses To High-fat Dietmentioning

confidence: 99%

“…Additionally, when adiposity matched, females display a greater volume of subcutaneous fat than males, whereas males have a greater volume of intra-abdominal or visceral fat (5, 9). Women are also known to have higher energy expenditure rates (47,49). Limited data exist explaining this, but they indicate increases in brown adipose tissue (BAT) in females (17), and recent studies demonstrate the role of estrogen in sex differences in muscle metabolism (40).…”

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

Griffin

Lanzetta

Eter

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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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...

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Section: Sexually Dimorphic Macrophage Responses To High-fat Dietmentioning

confidence: 99%

Section: Sexually Dimorphic Macrophage Responses To High-fat Dietmentioning

confidence: 99%

Section: Sexually Dimorphic Macrophage Responses To High-fat Dietmentioning

confidence: 99%

Section: Sexually Dimorphic Macrophage Responses To High-fat Dietmentioning

confidence: 99%

mentioning

confidence: 99%

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

Griffin

Lanzetta

Eter

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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Adipose tissue's rapid response team

Fried

2018

Journal of Leukocyte Biology

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Adipose tissues function in metabolic, endocrine, and immune roles to regulate energy balance and maintain health. Adipocytes reside within adipose tissues (so-called depots) together with fibroblasts, adipose progenitors, endothelial cells, and immune cells. Collaboration among these multiple cell types is necessary for the tissue to remodel and maintain homeostasis in the face of metabolic challenges. 1 In nonobese individuals, resident adipose tissue macrophages (ATMs) are mainly M2-like and function to remodel the tissue as needed for growth, maintenance, and repair. With chronic overnutrition and obesity, adipocytes expand in size to accommodate the need for energy storage and become dysfunctional. As a result, monocytes are recruited into adipose tissue in a CCL2 (MCP-1)-dependent manner. These ATMs localize around dead or dying adipocytes in the so-called crown-like structures, where they become M1 polarized and increase production of inflammatory cytokines. 2 The result is a feed-forward cycle within the adipose tissue, which is thought to lead to adipocyte metabolic and endocrine dysfunction, most notably excessively high release of potentially lipotoxic fatty acids and lower production of the antiinflammatory hormone adiponectin. The resulting adipocyte and systemic insulin resistance and dyslipidemia mechanistically links obesity to disease risk.Virtually all studies that led the macrophage recruitment hypothesis used obesity-prone male C57BL/6 mice fed a very high fat diet (HFD; usually 60% fat calories) for a prolonged period, at least 3 months, to induce obesity. However, analysis of the established obese state cannot reflect the dynamics of its development and hence its etiology, as Muir et al. 3 have accomplished in this issue ofThe author declares no conflict of interest

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Synergistic Modulation of Inflammatory but not Metabolic Effects of High‐Fat Feeding by CCR2 and CX3CR1

Zhang

Hinkle

O’Neill

et al. 2017

Obesity

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ObjectiveTo explore the impact of dual targeting of C-C motif chemokine receptor-2 (CCR2) and fractalkine receptor (CX3CR1) on the metabolic and inflammatory consequences of high fat diet (HFD)-induced obesity.MethodsC57BL/6J wild type (WT), Cx3cr1−/−, Ccr2−/− and Cx3cr1−/−Ccr2−/− double knockout male and female mice were fed a 45% HFD for up to 25 weeks starting at 12-weeks of age.ResultsAll groups gained weight at a similar rate and developed similar degree of adiposity, hyperglycemia, glucose intolerance and impairment of insulin sensitivity in response to HFD. As expected, the circulating monocyte count was decreased in Ccr2−/− and Cx3cr1−/−Ccr2−/−, but not in Cx3cr1−/− Mice. Flow cytometric analysis of perigonadal adipose of male, but not female, mice revealed trends to lower CD11c+MGL1− M1- like macrophages and higher CD11c−MGL1+ M2- like macrophages as a percentage of CD45+F4/80+CD11b+ macrophages in Cx3cr1−/−Ccr2−/− mice vs. WT mice, suggesting reduced adipose tissue macrophage activation. In contrast, single knockout of Ccr2 or Cx3cr1 did not differ in their adipose macrophage phenotypes.ConclusionAlthough CCR2 and CX3CR1 may synergistically impact inflammatory phenotypes, their joint deficiency did not influence metabolic effects of 45% HFD-induced obesity in these model conditions.

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Differences in Hematopoietic Stem Cells Contribute to Sexually Dimorphic Inflammatory Responses to High Fat Diet-induced Obesity

Cited by 93 publications

References 43 publications

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

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

Adipose tissue's rapid response team

Synergistic Modulation of Inflammatory but not Metabolic Effects of High‐Fat Feeding by CCR2 and CX3CR1

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