Ioannis Kyrou

Stress, Visceral Obesity, and Metabolic Complications

Abstract:  Stress is a state of threatened homeostasis or disharmony caused by intrinsic or extrinsic adverse forces and is counteracted by an intricate repertoire of physiologic and behavioral responses that aim to reestablish the challenged body equilibrium. The adaptive stress response depends upon an elaborate neuroendocrine, cellular, and molecular infrastructure, the stress system. Crucial functions of the stress system response are mediated by the hypothalamic‐pituitary‐adrenal (HPA) axis and the central and peripheral components of the autonomic nervous system (ANS). The integrity of the HPA axis and the ANS and their precise interactions with other CNS components are essential for a successful response to the various stressors. Chronic stress represents a prolonged threat to homeostasis by persistent or frequently repeated stressors and may lead to manifestations that characterize a wide range of diseases and syndromes. Such states progressively lead to a deleterious overload with complications caused by both the persistent stressor and the detrimental prolongation of the adaptive response. The metabolic syndrome can be described as a state of deranged metabolic homeostasis characterized by the combination of central obesity, insulin resistance, dyslipidemia, and hypertension. The incidence of both obesity and the metabolic syndrome in modern Western societies has taken epidemic proportions over the past decades and often correlates with indices of stress in the affected populations. Stress, primarily through hyperactivation of the HPA axis, appears to contribute to the accumulation of fat tissue, and vice versa, obesity itself seems to constitute a chronic stressful state and may cause HPA axis dysfunction. In addition, the description of obesity as a systemic low grade inflammatory condition that contributes to the derangement of the metabolic equilibrium implies that the proinflammatory cytokines which are secreted by the adipocytes hold a potentially important pathogenetic role. In this article we describe the physiology of the stress system response, with emphasis on metabolism, and review the recent data that implicate several neuroendocrine and inflammatory mechanisms mobilized during chronic stress in the development of the metabolic complications that characterize central obesity and the metabolic syndrome.

Circulating tumor necrosis factor alpha concentrations are higher in abdominal versus peripheral obesity

Fat tissue is a significant source of endogenous tumor necrosis factor alpha (TNFalpha), the pluripotent cytokine that plays an important role as a mediator of the peripheral insulin resistance found in obesity. The majority of evidence for this role of TNFalpha is from studies in animal models of obesity. To explore further the role of TNFalpha in the pathogenesis of obesity-related insulin resistance in humans, we compared plasma levels of TNFalpha and the other main endocrine cytokine, interleukin-6 ([IL-6] both measured by enzyme-linked immunosorbent assay), in 26 obese women (body mass index [BMI] > 30 kg/m2) and 13 female controls (BMI < 26 kg/m2) without a history of recent or active infection. Glucose and insulin levels were measured at 0, 1, and 2 hours after a 75-g oral glucose load. There was no significant difference in plasma TNFalpha or IL-6 levels between obese and non-obese subjects overall (2.10 +/- 0.19 v 1.65 +/- 0.18 pg/mL and 2.06 +/- 0.29 v 1.50 +/- 0.17 pg/mL, respectively). However, TNFalpha levels were significantly elevated in obese subjects with a 2-hour glucose level more than 140 mg/dL (n = 8) compared with the other obese subjects (n = 18) and the non-obese controls (2.88 +/- 0.46 v 1.75 +/- 0.10 and 1.65 +/- 0.18 pg/mL, respectively, P < .01). Furthermore, the TNFalpha level correlated significantly with the waist to hip ratio ([WHR] r = .53, P < .01) and fasting and post-oral glucose tolerance test (OGTT) insulin levels (r = .47, P < .02), but not with the BMI, and was higher in obese women with a WHR more than 0.90 (n = 14) in comparison to those with a WHR less than 0.90 (n = 12, 2.47 +/- 0.29 v 1.66 +/- 0.18 pg/mL, respectively, P < .03). The corresponding plasma leptin level was significantly higher in obese women versus the control group (41.6 +/- 2.5 v22.3 +/- 2.9 ng/mL, P < .001) and was related to the BMI (r = .60, P < .01) but not to TNFalpha or the WHR. There were no significant differences in the corresponding IL-6 concentration between groups, and IL-6 did not correlate with TNFalpha, leptin, BMI, WHR, or insulin levels. In conclusion, circulating TNFalpha levels are higher in abdominal obesity compared with peripheral obesity, and may contribute to the insulin resistance that more commonly complicates the former pattern of fat distribution.

Stress hormones: physiological stress and regulation of metabolism.

Stress, defined as a state of threatened homeostasis, mobilizes a complex spectrum of adaptive physiologic and behavioral responses that aim to re-establish the challenged body homeostasis. The hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS) constitute the main effector pathways of the stress system, mediating its adaptive functions. In western societies, indices of stress correlate with increasing rates of both obesity and metabolic syndrome which have reached epidemic proportions. Recent data indicate that chronic stress, associated with mild hypercortisolemia and prolonged SNS activation, favors accumulation of visceral fat and contributes to the clinical presentation of visceral obesity, type 2 diabetes, and related cardiometabolic complications. Reciprocally, obesity promotes a systemic low-grade inflammation state, mediated by increased adipokine secretion, which can chronically stimulate the stress system.

Dose-Dependent Effects of Recombinant Human Interleukin-6 on the Pituitary-Testicular Axis

Inflammatory cytokines are soluble mediators of immune function that also regulate intermediate metabolism and several endocrine axes. To examine the effects of interleukin-6 (IL-6), the main circulating cytokine, on the hypothalamic-pituitary-testicular axis in men, we performed dose-response studies of recombinant human IL-6 (rHuIL-6) in normal volunteers. Increasing single doses of IL-6 (0.1, 0.3, 1.0, 3.0, and 10.0 microg/kg body weight) were injected subcutaneously into 15 healthy male volunteers (3 at each dose) in the morning. We measured the circulating levels of testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and sex hormone binding globulin (SHBG) at baseline and then at 24 h, 48 h, and 7 days after the IL-6 injection. LH and FSH levels were also measured half-hourly for the first 4 h after the IL-6 injection. All IL-6 doses were tolerated well and produced no significant adverse effects. Mean peak plasma IL-6 levels achieved after IL-6 administration were 8 +/- 1, 22 +/- 5, 65 +/- 22, 290 +/- 38, and 4050 +/- 149 pg/ml, respectively for the five doses. We observed no significant changes in plasma testosterone levels after the two smaller IL-6 doses. The three higher IL-6 doses, however, caused significant decreases in testosterone levels by 24 h, which persisted at 48 h and returned to baseline by 7 days. The higher testosterone suppression was after the 3.0 microg/kg dose, making the dose-response curve bell-shaped. There also appeared to be small but not significant increases in LH levels after the three higher IL-6 doses, which were not acute and seemed to follow temporally the testosterone decreases. The concurrent plasma levels of FSH and SHBG were not appreciably affected by any IL-6 dose. In conclusion, subcutaneous IL-6 administration, which caused acute elevations in circulating IL-6 levels of a similar magnitude to those observed in severe inflammatory and noninflammatory stress, induced prolonged suppression in testosterone levels in healthy men without apparent changes in gonadotropin levels. This suggests that IL-6 might induce persistent testicular resistance to LH action or suppression of Leydig cell steroidogenesis or both, with potential adverse effects on male reproductive function.

Dietary and lifestyle interventions for weight management in adults from minority ethnic/non-White groups: a systematic review

Minority ethnic/non‐White populations are more prone to weight gain and more susceptible to obesity‐related complications. The objective of this study was to systematically review dietary and lifestyle interventions for weight management in minority ethnic groups. Electronic databases and reference lists of original studies and reviews were searched for studies on dietary and lifestyle weight management interventions published. Randomized clinical trials with ≥6‐month duration were included. Nineteen studies met the inclusion criteria. Fourteen studies involved African–Americans, one in non‐White Hispanics, one in Japanese Americans and three in both African–Americans and non‐White Hispanics. Most of the interventions proved relatively effective. However, significant drawbacks were noted for several of these studies, such as small sample size, high attrition rates and lack of follow‐up data. Better quality and long‐term trials are required in order to investigate in detail the effectiveness of lifestyle changes for weight management in these populations and eventually support evidence‐based recommendations.

Obesity in the elderly diabetic patient. Is weight loss beneficial? No

Obesity and type 2 diabetes constitute major public health issues in modern societies worldwide. Their prevalence on a global scale is alarming, and efforts to control their spread represent a priority of the public health agenda (1). Obesity is clearly driving a parallel epidemic of associated chronic diseases in all age-groups, including type 2 diabetes, hyperlipidemia, hypertension, atherosclerosis, obstructive sleep apnea, and liver dysfunction. Considerable attention is currently being focused on the consequences of obesity in vulnerable populations at both ends of the age spectrum, namely in youth and in the elderly. Elderly people, defined as individuals >65 years of age, comprise a substantial and growing part of the population in developed countries. Current demographic data in Western societies report that 12–15% of the general population is over the age of 65 years, and this proportion is projected to reach 20–25% by the year 2030 (2). Moreover, in the last 2 decades, the rate of obesity has risen dramatically among older adults, independently of sex, race, and educational level (3). This obesity epidemic significantly affects the health status of the geriatric population, since excess body weight in the elderly also correlates strongly with chronic ill health, poor quality of life, functional decline, disability, and dependency (4). Conversely, evidence suggests that obesity in the elderly is probably not associated with the same risks as in younger individuals, while in certain aspects, can even be protective (5). Furthermore, the prevalence of underweight is higher among older adults, who are also more vulnerable to unintentional weight loss either as a result of illness, or due to the aging process itself. The objective of this article is to assess the benefits relative to risks of weight loss that may be attained in the geriatric population, with special reference to the elderly diabetic patient. …

Peripheral mononuclear cell resistin mRNA expression is increased in type 2 diabetic women.

Resistin has been shown to cause insulin resistance and to impair glucose tolerance in rodents, but in humans its physiological role still remains elusive. The aim of this study was to examine whether resistin mRNA expression in human peripheral mononuclear cells (PBMCs) and its corresponding plasma levels are altered in type 2 diabetes. Resistin mRNA levels were easily detectable in human PBMC, and found to be higher in DM2 compared to healthy women (P = .05). Similarly, mononuclear mRNA levels of the proinflammatory cytokines IL-1β, TNF-α, and IL-6 were all significantly higher in DM2 compared to control women (P < .001). The corresponding plasma resistin levels were slightly, but not significantly, increased in DM2 women (P = .051), and overall, they correlated significantly with BMI (r = 0.406, P = .010) and waist circumference (r = 0.516, P = .003), but not with fasting insulin levels or HOMA-IR. Resistin mRNA expression is increased in PBMC from DM2 women, together with increased expression of the inflammatory cytokines IL-1β, TNF-α, and IL-6, independent of obesity. These results suggest that resistin and cytokines might contribute to the low-grade inflammation and the increased atherogenic risk observed in these patients.

Short-Chain Fatty Acid Acetate Stimulates Adipogenesis and Mitochondrial Biogenesis via GPR43 in Brown Adipocytes

Short-chain fatty acids play crucial roles in a range of physiological functions. However, the effects of short-chain fatty acids on brown adipose tissue have not been fully investigated. We examined the role of acetate, a short-chain fatty acid formed by fermentation in the gut, in the regulation of brown adipocyte metabolism. Our results show that acetate up-regulates adipocyte protein 2, peroxisomal proliferator-activated receptor-γ coactivator-1α, and uncoupling protein-1 expression and affects the morphological changes of brown adipocytes during adipogenesis. Moreover, an increase in mitochondrial biogenesis was observed after acetate treatment. Acetate also elicited the activation of ERK and cAMP response element-binding protein, and these responses were sensitive to G(i/o)-type G protein inactivator, Gβγ-subunit inhibitor, phospholipase C inhibitor, and MAPK kinase inhibitor, indicating a role for the G(i/o)βγ/phospholipase C/protein kinase C/MAPK kinase signaling pathway in these responses. These effects of acetate were mimicked by treatment with 4-chloro-α-(1-methylethyl)-N-2-thiazolylbenzeneacetamide, a synthetic G protein-coupled receptor 43 (GPR43) agonist and were impaired in GPR43 knockdown cells. Taken together, our results indicate that acetate may have important physiological roles in brown adipocytes through the activation of GPR43.

Hypothalamic-Pituitary-Adrenal Axis

3.

Weight management in overweight and obese patients with type 2 diabetes mellitus

Obesity is recognised as an important risk factor for type 2 diabetes, inducing insulin resistance and pancreatic beta-cell dysfunction. These obesity-related defects tend to progress following wei...