Regulation Of Adipokines Research Articles

Adipokines and dietary interventions in human obesity

Obesity is a multisystem disorder associated with cardiovascular and metabolic complications. According to recent studies, it is characterized as a condition of low-grade inflammation with altered adipose tissue function and secretion of various adipokines. One of the strategies in obesity treatment is dietary intervention (DI) that could modulate cytokine levels in a favourable way. The aim of this review was to summarize the results of studies performed in the last 13 years investigating DI programmes accompanied with weight loss in relation to profile of adipokines at different level (adipose tissue mRNA, adipose tissue secretion and circulating level) and identify whether modulations of adipokines are implicated in the positive effects of DIs. The overall finding is that DIs leading to 5-10% weight loss modulate production of certain adipokines and generally induce improvement of clinical parameters, e.g. insulin sensitivity, but the amelioration of obesity complications is not coherent with the pattern of adipokine regulation, except maybe for leptin. Global analysis of the adipose tissue secretome and measurement of panels of adipokines may prove more informative than studies on individual molecules.

Adipose tissue in renal disease: clinical significance and prognostic implications

Obesity is not only associated with the development of diabetes and hypertension, but is also a known risk factor for chronic kidney disease (CKD) and is a risk factor for progressive renal function loss. Abdominal obesity is especially related to incident CKD and mortality. The decline in fat mass over time has also been related to mortality in this population. In patients on peritoneal dialysis, intra-abdominal fat accumulation has been related to cardiovascular morbidity and mortality. The body mass index is a simple method to estimate fat mass in dialysis patients. Maximum abdominal circumference, triceps and subscapular skinfolds, and arm circumference have been proposed as alternative methods in assessing subcutaneous adipose tissue to overcome the altered hydration status associated with dialysis. Waist-to-hip ratio, waist-to-height ratio and the conicity index are used to estimate abdominal fat deposits. Dual-energy X-ray absorptiometry, bioelectrical impedance analysis, computed tomography and magnetic resonance imaging are more precise and reliable methods to estimate body composition in dialysis patients. Adipose tissue is the source of a novel group of hormonally active substances known as adipokines. Patients with CKD exhibit an increase in serum concentration of most of these substances. Besides, the kidney plays an important role in the regulation of adipokines, and altered renal handling of these substances might contribute to an increase in the uraemia-associated increased risk of cardiovascular disease and mortality. In particular, pro-inflammatory adipokines, such as leptin, tumour necrosis factor-alpha and inteleukin-6, have been associated with an increased risk of mortality, whereas the link between adiponectin, an antiatherogenic adipokine, and survival is controversial in patients with CKD.

Lifestyle and breast cancer: what advice for the management of post-cancer?

It is widely admitted that after adjuvant therapy, about one half of women with localized breast cancer experience a weight gain of 3 kg. It can however reach 8 to 10 kg in numerous cases. Risk factors associated with weight gain are unclear, but women undergoing chemotherapy seem to have an increased risk, especially before the menopause. Retrospective studies suggest that post-treatment weight gain might increase the risk of relapse. Furthermore, the only intervention trial in adjuvant breast cancer, though impaired by methodological pitfalls, suggests that limiting weight gain could increase disease free survival. The use of nutritional complements by cancer patients is usually underestimated. Several compounds, such as vitamins C and, E, selenium or carotenoids, have been investigated in clinical trials whose quality is usually poor. Available date nevertheless suggest a deleterious effect of supplementation with anti-oxydants, in particular at supraphysiological doses. The WHEL trial is the only large randomised trial investigating an healthy diet with vegetables, fruits and fiber after localized breast cancer. An effect of survival is observed in the experimental arm only in patients with sufficient level of physical activity. Physical activity, when practiced regularly, improves asthenia, quality of life and even survival, without any detrimental effect. It should however be initiated after an evaluation of patient’s ability and comorbidities, and be realized in specific centers with careful medical follow-up. Its mechanisms of action include regulation of estrogen, insulin, IGF1 and adipokines. Adapted physical activity should be proposed to patients fulfilling precise inclusion criteria.

Neonatal exposure to parathion alters lipid metabolism in adulthood: Interactions with dietary fat intake and implications for neurodevelopmental deficits

Organophosphates are developmental neurotoxicants but recent evidence also points to metabolic dysfunction. We determined whether neonatal parathion exposure in rats has long-term effects on regulation of adipokines and lipid peroxidation. We also assessed the interaction of these effects with increased fat intake. Rats were given parathion on postnatal days 1–4 using doses (0.1 or 0.2 mg/kg/day) that straddle the threshold for barely detectable cholinesterase inhibition and the first signs of systemic toxicity. In adulthood, animals were either maintained on standard chow or switched to a high-fat diet for 7 weeks. We assessed serum leptin and adiponectin, tumor necrosis factor-α (TNFα) in adipose tissues, and thiobarbituric acid reactive species (TBARS) in peripheral tissues and brain regions. Neonatal parathion exposure uncoupled serum leptin levels from their dependence on body weight, suppressed adiponectin and elevated TNFα in white adipose tissue. Some of the effects were offset by a high-fat diet. Parathion reduced TBARS in the adipose tissues, skeletal muscle and temporal/occipital cortex but not in heart, liver, kidney or frontal/parietal cortex; it elevated TBARS in the cerebellum; the high-fat diet again reversed many of the effects. Neonatal parathion exposure disrupts the regulation of adipokines that communicate metabolic status between adipose tissues and the brain, while also evoking an inflammatory adipose response. Our results are consistent with impaired fat utilization and prediabetes, as well as exposing a potential relationship between effects on fat metabolism and on synaptic function in the brain.

Adipokines: a review of biological and analytical principles and an update in dogs, cats, and horses

In addition to its role as an energy storage depot, adipose tissue is now recognized as a complex endocrine organ. Adipose tissue releases a variety of factors, termed adipokines, that regulate energy metabolism, cardiovascular function, reproductive status, and immune function. Some of the better-studied adipokines include leptin, adiponectin, and components of the renin-angiotensin system such as angiotensinogen. The function of more recently discovered adipokines such as resistin are under intense scrutiny. Abnormal production or regulation of adipokines occurs in obese individuals and is implicated in the development of a variety of associated co-morbidities including metabolic syndrome, type 2 diabetes, atherosclerosis, heart disease, and cancer in people, although evaluation in domestic species is just beginning. Adipokines are now being examined as potential biomarkers for risk assessment for development of complications related to obesity. This article summarizes the function and regulation of some better-characterized adipokines. It also reviews the current information on the characterization of adipokines in some domestic species in which rates of obesity and obesity-related disorders are increasing, such as the dog, cat, and horse.

Adiponectin and inflammation

LETTERS TO THE EDITORAdiponectin and inflammationGiamila FantuzziGiamila FantuzziPublished Online:01 Feb 2009https://doi.org/10.1152/ajpendo.90827.2008MoreSectionsPDF (29 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat to the editor: I am writing concerning the article “Adiponectin deficiency promotes endothelial activation and profoundly exacerbates sepsis-related mortality” by Teoh et al. (4). In the abstract, results, and discussion of the paper, the authors repeatedly assert that thioglycollate-injected adiponectin-knockout [APN-KO (in Ref. 4 Adipoq−/−)] mice have a “markedly greater” neutrophilic infiltrate in the peritoneal cavity and a “significantly greater” cytokine production compared with wild-type (WT) mice. However, the figures showing these data (Figs. 2 and 4 in Ref. 4) do not support these claims. In fact, no statistical significance is reported between thioglycollate-injected WT and APN-KO mice for either neutrophil numbers or cytokine levels. The graph bars seem to indicate that indeed the difference is not significant, perhaps with the exception of IL-12. Therefore, it appears incorrect to state that APN deficiency elicits “a heightened inflammatory response to thioglycollate-induced peritonitis,” as the authors do in the discussion. The results by Teoh et al. are actually in agreement with our recent data obtained in the closely related model of zymosan-induced peritonitis, in which we demonstrate that APN-KO mice have a response comparable to that of WT mice in terms of cytokine production and minor differences in terms of cellular infiltrate (3).Furthermore, Teoh et al. demonstrate that administration of recombinant mouse (rm)APN reduces inflammatory infiltrate and cytokine production in both WT and APN KO mice (Figs. 2 and 4 in Ref. 4). However, data presented on page E661 indicate that administration of rmAPN to WT mice did not increase circulating APN levels. Moreover, APN-KO mice injected with rmAPN had less than 50% serum APN compared with WT mice and yet had significantly lower inflammation than WT mice. Therefore, there seems to be no correlation between the the anti-inflammatory effects of rmAPN and its ability to raise circulating APN levels. This observation, together with data presented in their Figs. 2 and 4, appears to indicate that APN is not directly involved in regulating cytokine production and neutrophilic infiltrate in response to thioglycollate and that protection afforded by administration of rmAPN may be attributable to a nonspecific effect.Since the role of APN as a regulator of inflammation is currently the subject of debate (1, 2), it important that data on this topic be presented and discussed in an accurate fashion to reflect the actual obervations.REFERENCES1 Fantuzzi G. Adiponectin and inflammation: consensus and controversy. J Allergy Clin Immunol 121: 326–330, 2008.Crossref | PubMed | ISI | Google Scholar2 Lago F, Dieguez C, Gómez-Reino J, Gualillo O. Adipokines as emerging mediators of immune response and inflammation. Nat Clin Pract Rheumatol 3: 716–724, 2007.Crossref | PubMed | Google Scholar3 Pini M, Gove ME, Sennello JA, van Baal JW, Chan L, Fantuzzi G. Role and regulation of adipokines during zymosan-induced peritoneal inflammation in mice. Endocrinology 149: 4080–4085, 2008.Crossref | PubMed | ISI | Google Scholar4 Teoh H, Quan A, Bang KW, Wang G, Lovren F, Vu V, Haitsma JJ, Szmitko PE, Al-Omran M, Wang CH, Gupta M, Peterson MD, Zhang H, Chan L, Freedman J, Sweeney G, Verma S. Adiponectin deficiency promotes endothelial activation and profoundly exacerbates sepsis-related mortality. Am J Physiol Endocrinol Metab 295: E658–E664, 2008.Link | ISI | Google Scholar Download PDF Previous Back to Top Next FiguresReferencesRelatedInformationCited ByRole of Nutrition Support in Inflammatory Conditions28 March 2017 | Nutrition in Clinical Practice, Vol. 32, No. 3Successive Phases of the Metabolic Response to Stress25 March 2016Administration of IL-1ra improves adiponectin levels in chronic hemodialysis patients8 March 2014 | Journal of Nephrology, Vol. 27, No. 6Metabolic response to the stress of critical illnessBritish Journal of Anaesthesia, Vol. 113, No. 6Adiponectin levels in patients with psoriasis: A meta-analysis12 March 2013 | The Journal of Dermatology, Vol. 40, No. 6Adiponectin protects rat hippocampal neurons against excitotoxicity15 September 2010 | AGE, Vol. 33, No. 2 More from this issue > Volume 296Issue 2February 2009Pages E397-E397 Copyright & PermissionsCopyright © 2009 the American Physiological Societyhttps://doi.org/10.1152/ajpendo.90827.2008PubMed19171845History Published online 1 February 2009 Published in print 1 February 2009 Metrics

Current status of liver disease in Korea: Nonalcoholic fatty liver disease

Recently, obesity (BMI>or=25 kg/m2) and type II diabetes mellitus have reached epidemic proportions in Korea, and rates of nonalcoholic fatty liver disease (NAFLD) are between 10% and 25% of the general population. NAFLD in Korea is as closely associated with several components of metabolic syndrome including, obesity, hypertension, diabetes and dyslipidemia as it is in Western countries. Insulin resistance and hyperinsulinemia may play a role in the pathogenesis of fatty liver in patients with normal body weight as well as in patients with obesity. And, obesity induced accumulation of fat in the adipose tissue leads to an imbalance in the regulation of adipokines, such as downregulation of adiponectin and upregulation of retinol-binding protein 4 (RBP4) and ghrelin. High BMI, the AST/ALT ratio, and ALT levels could be used to distinguish NASH from simple steatosis in Korean patients. In large number of NAFLD patients who underwent a voluntary medical checkup, even a small weight reduction was associated with improvements in their hepatic steatosis grade on ultrasonography, serum aminotransferase levels, and related metabolic abnormalities. Subjects with fatty liver disease should be advised to lose weight through lifestyle modifications. Small animal and human studies of treatment with PPAR agonists and betaine have been reported in the Korean literature. It is now acknowledged that NAFLD is the most common liver disease in Korea, largely due to the considerable increase in metabolic abnormalities such as obesity and diabetes. Future studies should continue to focus both on the pathogenesis and the treatment of NAFLD in order to accumulate more of our own data.

Role of Estrogen Receptor‐α and −β in Regulating Leptin Expression in 3T3‐L1 Adipocytes

We investigated the effects of the estrogen receptor-alpha (ERalpha) and -beta (ERbeta) in the regulation of leptin, resistin, and adiponectin expression in 3T3-L1 adipocytes. Mature adipocytes were exposed to estradiol (E2), ERalpha agonist (PPT (4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol)), ERbeta agonist (DPN (2,3-bis(4-Hydroxyphenyl)-propionitrile)), E2 with ERalpha antagonist (MPP (1,3-Bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride)), and E2 with ERbeta antagonist (R,R-THC ((R,R)-5,11-diethyl-5,6,11,12-tetrahydro-2,8-chrysenediol)) at different concentrations. To clarify the expression and regulation of adipokines by ER subtypes, total RNA was extracted from cells and measured using quantitative PCR. Western blot analysis was performed to evaluate the protein expression of adipokines, ERalpha, and ERbeta. The leptin expression was significantly increased in the cells treated with high concentrations (10(-5) and 10(-6) mol/l) of the PPT (P < 0.01, P < 0.05). By contrast, the leptin expression decreased in a dose-dependent manner in the MPP-treated groups (P < 0.05). High concentrations (10(-5) mol/l) of R,R-THC with E2 (10(-7) mol/l) caused a significant increase of the leptin expression (P < 0.01). The leptin mRNA levels were positively correlated with the ERalpha mRNA levels (r = 0.584, P < 0.01) and negatively correlated with the ERbeta mRNA levels (r = -0.236, P = 0.03) in the adipocytes. The ratio of the ERalpha to ERbeta mRNA levels in the adipocytes was significantly associated with leptin mRNA levels (r = 0.454, P < 0.01). ERalpha induced leptin expression and ERbeta inhibited its expression in 3T3-L1 adipocytes. The ratio of the ERalpha-to-ERbeta expression in 3T3-L1 adipocytes may be an important potential regulatory factor in leptin expression.

Adipokines influencing metabolic and cardiovascular disease are differentially regulated in maintenance hemodialysis

Adipokines including leptin, adiponectin, visfatin, resistin, and interleukin (IL)-6 significantly influence energy metabolism, insulin sensitivity, and cardiovascular health. In the current study, we investigated serum levels of these adipokines in diabetic and nondiabetic patients on maintenance hemodialysis (MD) as compared with controls with a glomerular filtration rate greater than 50 mL/min. Serum leptin, adiponectin, high–molecular-weight (HMW) adiponectin, visfatin, resistin, and IL-6 were determined by enzyme-linked immunosorbent assay in control (n = 60) and MD (n = 60) patients and correlated to clinical and biochemical measures of renal function, glucose, and lipid metabolism, as well as inflammation. Adiponectin, visfatin, resistin, and IL-6 were significantly elevated in MD patients as compared with controls. In multivariate analyses, sex and body mass index were independently correlated with serum leptin levels in both controls and MD patients. Furthermore, insulin resistance was independently and negatively associated with adiponectin and HMW adiponectin in both groups. Moreover, circulating resistin levels were independently correlated with serum visfatin concentrations in control and MD patients. However, various independent associations were only found in either controls or patients on MD. Thus, serum IL-6 levels were strongly and independently associated with C reactive protein and resistin in MD patients but not control subjects. We show that levels of various adipokines are significantly increased in MD patients. Furthermore, regulation of adipokines in vivo strongly depends on renal function. Regulation of HMW adiponectin is similar as compared with total adiponectin in the patients studied.

Role and Regulation of Adipokines during Zymosan-Induced Peritoneal Inflammation in Mice

Adipokines, cytokines mainly produced by adipocytes, are active participants in the regulation of inflammation. Administration of zymosan (ZY) was used to investigate the regulation and role of adipokines during peritonitis in mice. Injection of ZY led to a significant increase in leptin levels in both serum and peritoneal lavage fluid, whereas a differential trend in local vs. systemic levels was observed for both resistin and adiponectin. The role of leptin in ZY-induced peritonitis was investigated using leptin-deficient ob/ob mice, with and without reconstitution with exogenous leptin. Leptin deficiency was associated with delayed resolution of peritoneal inflammation induced by ZY, because ob/ob mice had a more pronounced cellular infiltrate in the peritoneum as well as higher and prolonged local and systemic levels of IL-6, TNFalpha, IL-10, and chemokine (C-X-C motif) ligand 2 compared with wild-type mice. Reconstitution with exogenous leptin exacerbated the inflammatory infiltrate and systemic IL-6 levels in ob/ob mice while inhibiting production of TNFalpha, IL-10, and chemokine (C-X-C motif) ligand 2. In contrast with the important role of leptin in regulating each aspect of ZY-induced peritonitis, adiponectin deficiency was associated only with a decreased inflammatory infiltrate, without affecting cytokine levels. These findings point to a complex role for adipokines in ZY-induced peritonitis and further emphasize the interplay between obesity and inflammation.

Differential long-term dietary regulation of adipokines, ghrelin, or corticosterone: impact on adiposity

In the present experiment, we examined in Long-Evans rats the long-term effects of diets that differed in the energy provided by proteins (P) and fats (F) but provided a constant level of energy from carbohydrates (55%) on various hormones regulating feeding and metabolism. Sixty adult rats were fed for 2 months either a high-fat (protein-to-fat, PF 5/40), a control (PF 15/30), low-fat (PF 30/15), or high-protein (PF 40/5) diet ad libitum. Both the PF 30/15 and the PF 40/5 rats ate significantly less than their PF 5/40 and PF 15/30 counterparts throughout the experiment (P<0.001). PF 40/5 rats weighed less than PF 15/30 rats (PL=0.04). PF 40/5 and PF 30/15 rats had smaller epididymal and perirenal adipose tissue depots than PF 5/40 and PF 15/30 rats (P<0.05 or less). Adiponectin (+25-47%) and leptin levels in the PF 5/40 rats were higher than in the three other groups (P<0.0025 or less). Ghrelin concentration in the PF 30/15 group was also higher than in the three other groups (P<0.001 versus PF 5/40; P<0.05 versus PF 15/30 and PF 40/5). Corticosterone level was 2- to 2.5-fold higher in PF 40/5 rats than in the three other groups (P<0.01 or less). Immunoreactive insulin was not different between the four groups. Our current findings thus show that increases in the protein content resulted in a greater degree of leanness, but at sufficiently high levels, also activated the hypothalamo-pituitary axis. Ghrelin appeared to be down-regulated by increases in fat content and no obvious signs of insulin resistance were observed in any of the rats under study.

Evidence for parasympathetic innervation of white adipose tissue, clearing up some vagaries

to the editor: Recently, we reported that fat tissue receives not only sympathetic but also parasympathetic innervation ([5][1]). Using microsurgery, transneuronal retrograde tracing, and hyperinsulinemic euglycemic clamps, we demonstrated that parasympathetic innervation of fat tissue has an

Atherogenic dyslipidemia associated with metabolic syndrome and insulin resistance

Atherogenic dyslipidemia, a component of metabolic syndrome, is characterized by high levels of apolipoprotein B (apo B)-containing lipoproteins, including very-low-density lipoprotein remnants and small low-density lipoprotein particles, and reduced levels of high-density lipoprotein cholesterol. Although the National Cholesterol Education Program Adult Treatment Panel III includes elevations in blood pressure and plasma glucose in the definition of metabolic syndrome, the broader scope of metabolic syndrome includes proinflammatory and prothrombotic states, which derive from the secretory activity of adipose tissue. Abdominal fat can adversely affect insulin action and the disposal of glucose through an increase in the release of free fatty acid, resulting in accumulation of triglyceride in muscle and liver, thereby depressing insulin action and increasing output of apo B-containing lipoproteins. Impaired regulation of adipokines, bioactive substances secreted from adipose tissue, likely produces systemic inflammation, which can promote atherogenesis. Insulin resistance is recognized as an important metabolic defect linking the components of metabolic syndrome. One molecule that may play an important role in metabolic syndrome to regulate metabolic and vascular pathways is the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Studies have established PPAR-gamma deficiency as a cause of lipodystrophy and confirmed its adipogenic role. Patients with atherogenic dyslipidemia and metabolic syndrome should undergo global risk assessment for cardiovascular disease and future cardiovascular events to determine an overall treatment strategy.

Redefining Lipodystrophy Syndrome

Lipodystrophy syndrome comprises several conditions (lipoatrophy; lipohypertrophy; mixed syndrome, often associated with dyslipidemia; and insulin resistance). These conditions, though sometimes occurring together, may occur independently, suggesting a complex, multifactorial cause. To elucidate the relative contribution of risk factors of drug, disease, and host to fat redistribution, large epidemiologic studies using multivariate analysis were reviewed. In studies assessing lipoatrophy, the most common statistically significant risk factors were use of specific nucleoside analogues, increasing age, presence of markers of disease severity (CD4/HIV RNA), duration of therapy, and white race. In studies assessing lipohypertrophy, the most common statistically significant risk factors were duration of therapy, markers of disease severity, and protease inhibitor use. The pathogenesis of these disorders is complex, but recent hypotheses and evidence suggest that impairment to adipocyte differentiation, impairment of adipokine regulation, unopposed production of proinflammatory cytokines, dysregulation of 11-beta-hydroxysteroid dehydrogenase, and mitochondrial toxicity may play a role.

Independent Circadian and Sleep/Wake Regulation of Adipokines and Glucose in Humans

Leptin and adiponectin play important physiological roles in regulating appetite, food intake, and energy balance and have pathophysiological roles in obesity and anorexia nervosa. To assess the relative contributions of day/night patterns in behaviors (sleep/wake cycle and food intake) and of the endogenous circadian pacemaker on observed day/night patterns of adipokines, in six healthy subjects we measured circulating leptin, soluble leptin receptor, adiponectin, glucose, and insulin levels throughout a constant routine protocol (38 h of wakefulness with constant posture, temperature, and dim light, as well as identical snacks every 2 h) and throughout sleep and fasting periods before and after the constant routine. There were significant endogenous circadian rhythms in leptin, glucose, and insulin, with peaks around the usual time of awakening. Sleep/fasting resulted in additional systematic decreases in leptin, glucose, and insulin, whereas wakefulness/food intake resulted in a systematic increase in leptin. Thus, the day/night pattern in leptin is likely caused by combined effects from the endogenous circadian pacemaker and day/night patterns in behaviors. Our data imply that alterations in the sleep/wake schedule would lead to an increased daily range in circulating leptin, with lowest leptin upon awakening, which, by influencing food intake and energy balance, could be implicated in the increased prevalence of obesity in the shift work population.

Minireview: adiposity, inflammation, and atherogenesis.

Adipose tissue is a dynamic endocrine organ that secretes a number of factors that are increasingly recognized to contribute to systemic and vascular inflammation. Several of these factors, collectively referred to as adipokines, have now been shown regulate, directly or indirectly, a number of the processes that contribute to the development of atherosclerosis, including hypertension, endothelial dysfunction, insulin resistance, and vascular remodeling. Several adipokines are preferentially expressed in visceral adipose tissue, and the secretion of proinflammatory adipokines is elevated with increasing adiposity. Not surprisingly, approaches that reduce adipose tissue depots, including surgical fat removal, exercise, and reduced caloric intake, improve proinflammatory adipokine levels and reduce the severity of their resultant pathologies. Systemic adipokine levels can also be favorably altered by treatment with several of the existing drug classes used to treat insulin resistance, hypertension, and hypercholesterolemia. Greater understanding of adipokine regulation, however, should result in the design of improved treatment strategies to control disease states associated with increase adiposity, an important outcome in view of the growing worldwide epidemic of obesity.