Obesity, especially upper body obesity, is closely associated with diseases such as type 2 diabetes, dyslipidemia, and hypertension. The above disease names describe the metabolic syndrome i.e. a group of symptoms with insulin resistance as the central cause. The prevalence of obesity in the United States has increased dramatically in recent decades. Currently, the prevalence of obesity and metabolic syndrome is 33% and 24% respectively in the United States, and is also on the rise in developing countries. Both obesity and metabolic syndrome are important public health issues, and efforts are needed to understand these diseases and reduce their incidence. Modern societal lifestyles such as the Western diet, sedentary lifestyle, and environmental stress may contribute to the development of obesity and metabolic syndrome through abnormal regulation of the HPA axis, which contributes to positive energy balance. Stress Response: Stress is an attack by a living organism on the homeostasis of its natural internal environment, whereby the animal produces a physiological stress response to restore the homeostasis lost due to the stressor. The stress response is characterized by acute behavioral and physical adaptations: including heightened cognition, pain deficit, glycogen isomerization, lipolysis, and inhibition of reproduction. Positive stress responses include the fight or flight response, i.e., either confronting the stressor or fleeing from confronting the stressor. In modern society, the negative response is the predominant form of stress response, i.e., the individual neither engages in fight nor flight and ultimately loses the confrontation response, and this negative response is associated with changes in the HPA axis. The stress response consists of two main components: 1. the autonomic nervous system, including the sympathetic and parasympathetic nervous systems; 2. the HPA axis. Both are key elements of the stress response, and this article will focus on the role of the HPA axis in stress-related obesity and metabolic diseases. Stress can be induced by both external stressors (e.g., employment, social pressures) and internal body stressors (e.g., sleep deprivation). Acute short-term stress responses are necessary for the restoration of homeostasis in the internal environment, whereas chronic or long-term stress responses are detrimental and may lead to a number of disease states. A study in women reported that a history of depression was associated with HPA axis hyperfunction and reduced bone mineral density. A study of stress and the risk of obesity and other metabolic diseases in non-human primates, fed an atherosclerosis-inducing diet to female monkeys living in groups, showed that low-status animals (which were more likely to be subjected to aggression and to develop a stress response) had a higher proportion of visceral adipose tissue (VAT) than subcutaneous adipose tissue (SAT) (suggestive of upper body obesity), higher rates of atherosclerosis, and lower rates of ovarian insufficiency. ovarian insufficiency were all more prevalent than in non-low-status animals. Hypothalamic-pituitary-adrenal axis The HPA axis is one of the two major neuroendocrine systems associated with the stress response. The release of corticotropin-releasing hormone (CRH) from the paraventricular nucleus of the hypothalamus stimulates the synthesis of adrenocorticotropic hormone (ACTH) in the anterior pituitary gland. The paraventricular nucleus of the hypothalamus also produces arginine pressin and oxytocin, which promote ACTH secretion. Stressors in the body such as hypoglycemia, hemorrhage, and immune stimulation activate neurons in the paraventricular nucleus to express argipressin and CRH .ACTH stimulates the production of cortisol in the adrenal cortex. In addition to these mechanisms of HPA axis activation, studies in the last 15 years have demonstrated that cytokines produced by immune cells or adipocytes stimulate the HPA axis at the level of the hypothalamus, the anterior pituitary and the adrenal cortex. In the blood circulation, cortisol is transported to peripheral target tissues in the form of binding to corticosteroid-binding globulin (CBG). In peripheral target tissues, the effectiveness of cortisol depends on the activity of 11β-hydroxysteroid dehydrogenase (11β-HSD).Type 1 11β-HSD converts inactive cortisol to active cortisol, whereas type 2 11β-HSD converts cortisol to inactive cortisol. Evidence that cortisol concentrations may be associated with obesity and metabolic disease was first established by clinical observations in Cushing’s syndrome. Hypercortisolemia in patients with Cushing’s syndrome is strongly associated with upper body obesity, glucose intolerance (impaired glucose tolerance), and hypertension. The implementation of adrenalectomy to reduce cortisol concentrations reverses the symptoms of impaired glucose tolerance and obesity in patients with Cushing’s syndrome. Studies in the last decade have confirmed that obesity and metabolic syndrome are characterized by a chronic inflammatory response. Cytokines that promote the inflammatory response excite the HPA axis, and conversely, cortisol reduces the production of cytokines and other inflammatory mediators. Thus, there must be some connection between the HPA axis and the inflammatory response; however, the nature of these relationships remains to be further substantiated. Cortisol Response in Obese Patients A large number of clinical studies have been conducted on the role of the HPA axis in the average obese patient. Early findings were less consistent. When patients with upper-body obesity were compared with emaciated or lower-body obese patients, the study data were more consistent. pasquali et al. demonstrated an increase in 24-hour urinary free cortisol excretion in women with upper-body obesity compared with women with lower-body obesity. Similarly, Rosmond et al. reported that there was a significant correlation between postprandial salivary cortisol levels and diagnostic indicators of metabolic syndrome such as body mass index, waist-to-hip ratio, fasting glucose, insulin, triglycerides, cholesterol, and blood pressure in men. It has also been shown that 24-hour urinary free cortisol is increased in women who are obese due to a stressful event (stress-related obesity) compared to women who are not stress-related obese (age-matched and weight-matched to the former) or who are emaciated, suggesting an overactivation of the HPA axis in stress-related obesity. Tissue-specific cortisol metabolism: role of 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) in adipose tissue Expression of 11β-HSD1 in peripheral tissues, including hepatic and adipose tissues [46], is important for the activity of the HPA axis, and the regeneration of intracellularly active cortisol, and the expression of 11β-HSD1 in adipose tissues regulates local cortisol levels, which may play a role in obesity and the Masuzaki et al. found that 11β-HSD1 was overexpressed in adipose tissue of mice fed a high-fat diet, which eventually led to abdominal obesity and metabolic syndrome. Related human studies reported that in obese individuals 11β-HSD1 expression was altered in specific adipose tissues, and that obese individuals had significantly increased 11β-HSD1 expression in subcutaneous adipose tissues compared with emaciated individuals. The changes in specific adipose tissue reservoirs may be related to the regulation of 11β-HSD1. Whereas specific adipose tissue reservoirs differentially express TNF-α, leptin, and adipokines, these cytokines can stimulate the expression of 11β-HSD1. Early Experience of Stress and Obesity Experiencing stress early in life may also be a risk factor in the development of obesity and metabolic syndrome. A recent study in non-human primates reported that young macaques (3-5 months) whose mothers faced dietary insecurity exhibited higher body weight, body mass index, waist circumference, and insulin resistance during adolescence. One hypothesis concerns the “fetal plan”: the idea that the growth and development of the fetus in utero predicts its body mass index and propensity for obesity in adulthood. This hypothesis suggests that the specific stresses caused by maternal malnutrition during pregnancy, which result in low birth weight, may increase the risk of obesity and metabolic diseases in adulthood, and the Dutch famine of 1944 has been extensively studied to evaluate this hypothesis. Analyses of birth weight and metabolic diseases have found that experiencing starvation in utero leads to an increased incidence of obesity [86,87] and diabetes [88] in adulthood. Sleep deprivation and obesity Over the past 30 years, the average number of hours of sleep per night has decreased from 8-9 hours to 7 hours. Currently, 30% of adults in the United States sleep less than 6 hours at night. Sleep deprivation is associated with the risk of developing obesity and type 2 diabetes. Several epidemiologic studies have reported that body mass index is negatively associated with sleep duration in adults and children [103,104]. In some experimental studies, insulin sensitivity was reduced in sleep-restricted individuals. Sleep deprivation is recognized as a chronic stressor that may contribute to an increased risk of obesity and metabolic diseases, and the mechanism may be partly through abnormal regulation of the HPA axis. Conclusions Animal models in the current study provide evidence for the relationship between stress, the HPA axis, and metabolic disease, but human studies of changes in the HPA axis are more subtle. Overnutrition, sedentary lifestyle, and sleep deprivation are typical of modern society, and chronic exposure to environmental stress potentially promotes the development of obesity. This may be mediated, at least in part, through the HPA axis, although the relationship is complex and many factors including: genetic polymorphisms, tissue specificity of aldosterone metabolism, chronic inflammatory responses, leptin, ghrelin, and sex hormones can influence the strength of this relationship. Further research should focus on addressing the mechanisms by which aberrant HPA axis activity contributes to obesity and other metabolic complications, explaining in detail the causal relationship between chronic stress and obesity, and ultimately leading to effective therapeutic or preventive measures.