Added: Margaux Shover - Date: 26.02.2022 10:58 - Views: 36512 - Clicks: 5695
Once thought to simply be a nutritional disorder, obesity has become a major health concern characterized by a state of constant low-grade inflammation caused by chronic adiposity. When left untreated, obesity can lead to a of diseases including, but not limited to, cardiovascular disease, metabolic syndrome, neurodegeneration, type II diabetes mellitus, chronic kidney disease, and infertility. The distribution of adiposity differs in men and women, and these differences, along with the differences in sex hormones and sex hormone levels, can exacerbate or attenuate the course of disease pathology.
Obesity can also be exacerbated by stress, which can worsen disease pathogenesis. In this review, we will explore how obesity affects inflammation and disease and how sex can affect the course of these diseases. Translational Studies on Inflammation. Obesity has been associated with an elevated risk of type II diabetes, cancer, neurodegeneration, infertility and stress hypertension, and cardiovascular disease CVD [ 23 ].
The increased risk for various health risks is due in part to the inflammatory adipokines produced by the adipose tissue itself. Clinically, body mass index BMI is the most widely used tool to measure adiposity. However, BMI measures total mass, including both fat and fat-free lean mass, so it is a poor indicator of adiposity [ 2 ]. Further, the different compartments of fat and different types of adipose tissue within these compartments play a major role in the overall increased health risks associated with increases in adiposity [ 4 ]. Lastly, the body composition differs between men and women; men have more lean mass than women, whereas women have more fat mass.
In this book chapter, we help to unravel the differences in adipose-induced inflammation in men and women and how these differences may contribute to various pathophysiologies. Adipose tissue is composed of a variety of cells, including adipocytes, macrophages, leukocytes, endothelial cells, and fibroblasts.
This metabolic tissue and the subsets of cells found within this tissue play a role in both the inflammatory and hormonal pathways. This has led many to believe that adipose tissue is a novel endocrine organ [ 5 ]. Classically adipocytes were believed to be either white or brown adipocytes. The white adipose tissue WAT is the adipose tissue which is often focused on in obesity research. The WAT is less metabolically active, is composed primarily of stored triglycerides, and produces adipokines which regulate hunger, satiation via leptin, breakdown of triglycerides via adiponectin, and insulin sensitivity via IL-1 and IL-6 [ 5 ].
Interestingly, these adipokines become dysregulated in obese states which can further exacerbate cellular and systemic dysfunctions [ 6 ]. The increase in inflammatory cytokines is a contributing factor to the various pathophysiologies discussed within this chapter. Brown adipose tissue BAT is colored brown due to the high mitochondrial content. This highly metabolically active tissue also plays a role in thermogenesis, classically in neonates, and in lipid breakdown [ 7 ].
Recent studies have shown that BAT is not only found in neonates but can also be found in adults. A study conducted in males and females using PET-CT scans detected BAT tissue in the fascial plane in the ventral trunk and superficial and lateral sternocleidomastoid muscles [ 10 ].
Further, this study showed that there were differences in BAT mass in males and females, with females having more BAT than males. The sex hormones, most notably testosterone androgen in males and estrogen and progesterone in females, play a role in fat deposition, metabolism, and energy balance within their respective sex.
We will briefly discuss the specific roles of the sex hormones as they relate to adipose tissue. Estrogen has been shown to have both anti-inflammatory and antioxidant properties and can regulate metabolism [ 12 ].
Much of the data supporting estrogen as a protective factor comes from differences observed between pre- and postmenopausal women, where women in the pre-menopausal phase are protected against many cardiometabolic diseases, until they reach the menopausal period, where there is an increase in CVDs, inflammation, and weight gain [ 13 ].
Low testosterone levels in men have also been associated as a risk factor for pathophysiologies, including sexual dysfunction, CVD, insulin sensitivity, and type II diabetes [ 14 ]. Conversely, high levels of estrogen in men and high levels of testosterone in women have been shown to have negative effects on weight gain [ 15 ].
High levels of testosterone, seen in women with polycystic ovarian syndrome PCOSor low levels of estrogen seen in postmenopausal women have been linked to increased weight gain, specifically in the intra-abdominal fat [ 16 ]. Further, in men, testosterone replacement, when there are low levels of testosterone, has been shown to increase lean body mass and improve lipid and cholesterol levels [ 1718 ]. More recent studies have shown that while both estrogen and androgens are important for many physiological processes, the estrogen to androgen ratio is important in regulating adipose tissue deposition.
An important step in the production of estrogen is the enzyme aromatase, which converts testosterone to estrogen. Both male and female aromatase null mice exhibited increased weight gain and obesity-related metabolic complications [ 20 ]. Together, these data suggest that both estrogen and testosterone play an important role in regulating obesity and adiposity. As stated ly, the body composition differs between men and women. Men are more likely to accumulate adipose tissue around the trunk and abdomen, whereas women usually accumulate adipose tissue around the hips and thighs [ 2122 ].
Women have a higher percentage of body fat than lean fat when compared to men who have the same BMI. Therefore, the health consequences are different for each gender at the same BMI [ 21 ]. In addition, a higher portion of that fat is in the femoral-gluteal region as compared to the abdominal region for men [ 22 ]. Studies have shown that the relative distribution of fat has a greater impact on CVD risks than total excess body fat.
The female pattern of fat distribution, around the femoral-gluteal area, is relatively protective, compared to the male pattern of abdominal fat accumulation [ 232425 ]. Within the abdomen, fat can accumulate in the subcutaneous area, subcutaneous adipose tissue SATor, in the deep abdomen, visceral adipose tissue VAT.
These changes can cause further inflammatory cascades, including inducing proinflammatory macrophages into the adipose tissue Figure 1. These inflammatory cells exacerbate adipose tissue cytokine production or increase disease risks, which can further feed into this cycle. The effects of lean vs. A healthy diet and exercise are characterized by lean adipose tissue. Lean adipose tissue aids in regulating inflammation by secreting anti-inflammatory cytokines as well as secreting high levels of adiponectin which aids in insulin sensitivity [ 27 ].
Leaner adipose tissue also secretes low levels of leptin and resistin. Conversely, obese adipose tissue release high levels of resistin and leptin which promote insulin insensitivity. Obese adipose tissue also exhibits a proinflammatory cytokine profile which can lead to diseases such as diabetes and neurodegeneration. Men tend to have a greater ratio of lean to obese adipose tissue since they have greater muscle mass compared to women who have more obese adipose tissue [ 28 ]. Multiple studies have also shown that VAT is associated with a higher cardiovascular risk [ 2425 ]. Since the VAT has primarily been associated with the abdominal region, the VAT has historically played a more pathogenic role in male pathology.
Because of the high rate of obesity in the United States, and the increased VAT deposition seen in both men and women, we understand that VAT deposition also increases risks in females. Therefore, more therapeutic interventions are needed to inhibit VAT deposition in both men and women. Considerable amounts of data indicate that sex-specific differences in both acute and chronic inflammatory responses exist between males and females across multiple species and that these differences are altered with advancing age.
While it appears clear that variations between the sexes do exist and these variations change with aging, the exact fluctuations in inflammatory biomarkers, both between sexes and with aging, are not fully elucidated. Complicating matters is the established role of adipose tissue as a source of both pro- and anti-inflammatory cytokines. Leptin, adiponectin, and other cytokines synthesized and secreted by adipose tissue have been shown to play a profound role in modulating both systemic and localized inflammatory reactions.
Another complicating factor regarding inflammatory responses between males and females is the potential role of steroid hormones in various sex-specific physiological responses, including accumulation and storage of adipose tissue, and inflammation.
Estrogen has been shown to have potent anti-inflammatory activity and cardioprotective effects in females, and as estrogen levels decline with age after the onset of menopause, these protective effects of estrogen are minimized [ 1230 ]. While much has been determined, further study into the sex-specific differences between males and females, how these levels change over time with aging in a sex-specific manner, and the role that these levels and their changes play in both acute and chronic diseases are warranted.
Many biomarkers of inflammation have been investigated regarding adiposity, age, sex, and ethnic variations. Data from a meta-analysis investigating potential relationships between the adipose tissue-derived cytokines leptin and adiponectin and inflammatory biomarkers including CRP, IL-6, and TNF-alpha suggested a positive correlation between leptin and all three inflammatory biomarkers, whereas there was a negative correlation with respect to adiponectin and the biomarkers [ 31 ].
When adjusted for age, Grassman et al. In contrast to other studies, the authors found no ificant differences when looking at sex and inflammatory markers in relation to adipose tissue. In another study aimed at elucidating mechanisms responsible for differences in inflammatory responses across sexes, Wegner et al. Interestingly, increases in circulating plasma cortisol levels were also found to be ificantly elevated in women as compared to men, which could play a role in the heightened response.
In contrast Kuo et al. Older male mice showed ificantly higher levels of pro-inflammatory markers IL-6, IL, and TNF-alpha than age-matched female mice upon stimulation with endotoxin. In younger mice, however, they did not find a gender-specific difference in these same biomarkers. An investigation of factors associated with biomarkers of systemic inflammation using age- sex- and body mass index BMI -adjusted linear regression found an age-related effect on the markers. When they looked at sex-specific differences, the were varied, with CRP and IL-6 levels being lower among men.
In looking at sex-specific differences of oxidative stress and inflammation with regard to cardiovascular risk factors in Arab populations, Khadir et al. In order to look at the relative impact of central obesity versus general obesity, the authors adjusted for age, BMI, and gender and noted that the levels of IL-6, TNF-alpha, and ROS were associated with central obesity but not general obesity, further suggesting that sex-specific patterns of adipose distribution can potentially for some of the observed sex-specific differences in males versus females.
The authors concluded that the relative contribution of inflammation and oxidative stress to CVD in Arab populations was linked, at least in part, to gender-specific distributions of body fat [ 35 ]. While it is well known that obesity is a risk factor for many diseases, it is important to understand that the chronic state of inflammation associated with obesity further exacerbates obesity itself. Therefore, in many cases, obesity and inflammation increase pathophysiology, and these pathophysiologies further exacerbate the inflammation and obesity in a continuous vicious cycle.
Below we describe the role of the sex hormones on obesity-induced inflammation in metabolic syndrome, CVD, type II diabetes, chronic kidney disease CKDneurodegeneration, cancer, infertility, and stress. Metabolic syndrome MetSalso known as syndrome x, is a health condition characterized by insulin resistance, glucose intolerance, hypertension, high triglycerides, low HDL cholesterol, abdominal obesity, dyslipidemia, and inflammation [ 36 ]. The increased incidence of MetS has been linked to obesity and a lack of physical activity [ 37 ]. This emphasizes that prevention, rather than treatment, is the key to reducing the prevalence of metabolic syndrome in those at risk and those who are pre-symptomatic.
Diagnostic criteria for metabolic syndrome vary among organizations but typically include blood pressure, a large waist circumference, and the following: high levels of triglycerides and blood glucose and low levels of high-density lipoprotein cholesterol [ 263739 ]. Interestingly, there is no difference in prevalence of MetS between men and women, but there are differences in symptoms among men and women; women are more likely to have abdominal obesity, whereas men have more varied symptoms [ 36 ].
As ly described, intra-abdominal obesity is not classically associated with women and, therefore, may play a more pronounced role in this gender. Further, it has been shown that women throughout their lives have consistently higher levels of adiponectin which increases insulin sensitivity and leptin, which als fullness to the brain than males.
This implies that the adipose tissue in women produces adipokines which play a role in female adipose deposition and regulation [ 40414243 ]. It is well known that brown adipose tissue BAT is characterized by the expression of UCP-1 which causes an increase in mitochondrial function and metabolism [ 4445 ].
Further, in oxidative phosphorylation, genes, responsible for assisting in transcriptional activation in the mitochondria, have increased levels of expression in women [ 41 ].
The upregulation of this UCP-1 and increases in oxidative phosphorylation genes indicate that women express more metabolically active fat mass in comparison to men. Understanding that women have more metabolically active fat may help to explain the differing symptoms seen in MetS between men and women. MetS and obesity can induce changes in gene expression. Genetic SNP predispositions within this receptor, which are found in women, have been linked to increased susceptibility for obesity and insulin resistance [ 46 ] Estrogen can also activate a variety of metabolism genes, which play a role in the increased fat metabolism in humans and rodents [ 4447 ].
Women in the postmenopausal period, when estrogen levels have decreased, have a higher incidence in central adiposity and a higher risk for developing MetS [ 48 ]. Contrastingly, throughout life men have larger muscle mass and less free fat in organs that are highly metabolically active like the kidneys, liver, and brain. Males are more likely than women to experience an increase in incidence of diabetes due to decreases in insulin sensitivity [ 46 ]. Men also have lower expression of oxidative phosphorylation genes and brown adipose tissue, as indicated by UCP1, compared to women [ 49 ].
Taken together, these data support the idea that men and women present with different symptoms of metabolic syndrome and, therefore, may need different treatments for MetS consistent with these symptoms. According to the American Heart Association, CVD is a term that encompasses many conditions including heart disease, heart valve issues, heart failure, and stroke.
CVD is the leading cause of death for a variety of US ethnic populations [ 50 ]. Further, there are differences in the prevalence of CVD among race, sex, and hormone levels [ 50 ]. Classically, men have higher levels of CVD than women, until women reach the postmenopausal period, the sixth decade of life, where women have similar or higher incidence of CVD than males of the same age [ 50 ]. Obesity, specifically abdominal adiposity, is a main risk factor for CVD. Further, Garcia et al.
Therefore, reducing and preventing obesity could be a critical method for mitigating cardiovascular-related disorders in both men and women. Fat accumulation of the neck has been found to be a strong predictor of CVD [ 53 ]. Fat accumulation is usually estimated via the measuring the neck circumference. In contrast to the well-defined and studied compartments and sex differences in accumulation with the abdominal fat deposition, less is known about these factors in the neck.
In one retrospective study, overweight and obese women have more subcutaneous neck fat compared to men even after age and BMI matching.
In the same study, subcutaneous neck fat was associated with higher incidence of metabolic risk than intermuscular fat deposits in both sexes [ 54 ]. This suggests that similar to abdominal fat, women have more subcutaneous fat and men more intermuscular fat in the neck. Obesity creates an inflammatory state of the body that affects heart health.
However, the overall effects may differ among the sexes based on sex hormone activity. Men have a higher overall incidence of death due to CVD [ 50 ]. Activating the innate immune system, specifically the immune cell, the macrophages, induces inflammation and increases the risk for developing atherosclerosis [ 46 ]. Therefore, by inheriting a Y chromosome, men increase their genetic risk for developing CVD. Data suggests that testosterone does not confer any protection against obesity, inflammation, and CVD [ 46 ].
Levels of the sex hormone estrogen do not appear to affect men as severely as women [ 46 ]. It is hypothesized that the gender difference of varying estrogen levels only becomes evident in postmenopausal women who have lower levels of this sex hormone. Treatment and prevention methods using statins for CVD have been targeted more at men than women, as deemed appropriate by the American Heart Association. However, guidelines have recently been tailored to be more gender-inclusive based on cardiovascular risk factor assessments [ 52 ].Fat women sex Norman
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Sex Differences in Obesity-Induced Inflammation