ReviewSexual differences in the control of energy homeostasis
Introduction
The increasing prevalence of obesity throughout the world [51], [122], [127] is associated with an escalating incidence of obesity-related disorders and health costs [5]. Obesity is a leading cause for the development of adverse metabolic effects, including non-insulin dependent diabetes mellitus, dyslipidemia, and cardiovascular disease [34], [45]. It has been estimated that 47 million individuals in the United States have obesity-related metabolic diseases [53]. There are important sex differences in the prevalence of these metabolic diseases. Women under the age of 50 have much less obesity-related metabolic disorders; however, the prevalence of these metabolic disorders increases dramatically in women after menopause [52]. Children who have metabolic diseases have a higher risk of developing adverse events later in life [55], [116]. In today’s society there is an increase in the prevalence of obesity and its related metabolic diseases in adolescents and it is significantly higher among males than females aged 12–18 years [54], [70], [154]. Data suggest that ovarian hormones may be protective against the metabolic syndrome because prior to menopause, the prevalence of the metabolic disorders is higher among males than females; however, after menopause, women are more likely to suffer from metabolic disorders.
The increased health risks due to obesity vary depending on the location/accrual of adipose tissue [15], [16], [17], [19], [123]. Specifically, adipose tissue distributed in the abdominal or visceral region carries a much greater risk for metabolic disorders, than does adipose tissue distributed subcutaneously [19], [20], [21]. Differences in distribution of adipose tissue and the relative risk for diseases suggest that not all adipose tissue is created equally. Rather, different adipose depots have different properties that can have important consequences on health outcomes.
There are distinct sex-dependent differences in the regional fat distribution. If age and body mass index (BMI) are matched, women have lower waist-to-hip ratio, indicating a greater amount of subcutaneous adipose tissue than men do [95], [117]. Excess adiposity in the central visceral region of the body (‘android’ or male-pattern obesity [167]) is correlated with increased risk and mortality from disorders including diabetes, hyperlipidemia, hypertension, and atherosclerosis [11], [56], [73]. In contrast, excess adiposity in the gluteal/femoral subcutaneous region (‘gynoid’ or female-pattern) is poorly correlated with risk for these metabolic disorders [18], [39], [40], [88], [123]. Hence, there are sex-based differences with regard to obesity-associated health risks with obese men being more likely to develop secondary metabolic complications and cardiovascular diseases than obese women [36], [83], [87], [92], [169]. Therefore, the distribution of fat is more directly associated with the metabolic syndrome than total body fat.
There are two important implications that follow from these observations. The first is that males and females may differ in their susceptibility to the metabolic syndrome based on where they deposit adipose tissue. The second is that whereas we know the health consequences associated with visceral fat deposition, very little is known about how excess nutrients are partitioned/stored into the different adipose tissue depots. The goal of this review is to explore what we know about these sex differences in energy balance which are associated with adipose tissue accrual and deposition, as well as the role that sex hormones play in these differences.
Section snippets
Sex steroids regulate fat distributions
As previously mentioned, on average, women carry more fat subcutaneously [42], [66], [80], [89], [90]; whereas men carry more fat viscerally [167]. Gonadal/sex steroids have been proposed as regulators of fat distribution [47], [48]. Men have lower estrogen, and on average, men also have less total fat and a more central or intra-abdominal distribution; whereas premenopausal women have more total fat and a more gluteal/femoral subcutaneous fat distribution (Fig. 1). Intra-abdominal fat varies
Energy balance regulation
Obesity is a disorder of energy homeostasis. However, most animals match caloric intake with caloric expenditure quite precisely, resulting in relatively stable fat stores [74], [77]. An organism’s ability to regulate energy homeostasis requires that there is an ability to sense changes in energy flux and the central nervous system (CNS) must be a key player in both the sensing and responding to changes in energy flux. Key to the ability to sense this change in energy flux are signals
Sexual dimorphism in regulation of energy balance
The phenomenon of maintaining typical sex-specific fat distributions in males and females suggests sex-specific mechanisms that regulate energy balance and adiposity. Male and female rodents use different behavioral and metabolic strategies to regulate energy balance. When overfed voluntarily with a palatable high fat diet chronically [137] or acutely [138], female rats gain more body weight than males due to greater conservation of energy expenditure with lower activation of thermogenesis in
Summary
Sex specific distribution of body fat has important implications for how obesity influences a wide variety of co-morbid conditions. A wide range of evidence links these differences in body fat distribution to gonadal steroids that also have important effects on the regulation of energy balance. As a result, males and females also appear to have important differences in the systems that regulate energy balance and body weight. Specifically, females store energy in the subcutaneous depot when
Acknowledgment
This work is supported by NIH Grant DK73689 to D.J.C.
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