Adipose Tissue Remodeling in Obesity: An Overview of the Actions of Thyroid Hormones and Their Derivatives.
Pharmaceuticals (Basel, Switzerland)
Metabolic syndrome and obesity have become important health issues of epidemic proportions and are often the cause of related pathologies such as type 2 diabetes (T2DM), hypertension, and cardiovascular disease. Adipose tissues (ATs) are dynamic tissues that play crucial physiological roles in maintaining health and homeostasis. An ample body of evidence indicates that in some pathophysiological conditions, the aberrant remodeling of adipose tissue may provoke dysregulation in the production of various adipocytokines and metabolites, thus leading to disorders in metabolic organs. Thyroid hormones (THs) and some of their derivatives, such as 3,5-diiodo-l-thyronine (T2), exert numerous functions in a variety of tissues, including adipose tissues. It is known that they can improve serum lipid profiles and reduce fat accumulation. The thyroid hormone acts on the brown and/or white adipose tissues to induce uncoupled respiration through the induction of the uncoupling protein 1 (UCP1) to generate heat. Multitudinous investigations suggest that 3,3',5-triiodothyronine (T3) induces the recruitment of brown adipocytes in white adipose depots, causing the activation of a process known as "browning". Moreover, in vivo studies on adipose tissues show that T2, in addition to activating brown adipose tissue (BAT) thermogenesis, may further promote the browning of white adipose tissue (WAT), and affect adipocyte morphology, tissue vascularization, and the adipose inflammatory state in rats receiving a high-fat diet (HFD). In this review, we summarize the mechanism by which THs and thyroid hormone derivatives mediate adipose tissue activity and remodeling, thus providing noteworthy perspectives on their efficacy as therapeutic agents to counteract such morbidities as obesity, hypercholesterolemia, hypertriglyceridemia, and insulin resistance.
10.3390/ph16040572
Cardio-Metabolic Effects of High-Fat Diets and Their Underlying Mechanisms-A Narrative Review.
Nutrients
The majority of the epidemiological evidence over the past few decades has linked high intake of fats, especially saturated fats, to increased risk of diabetes and cardiovascular disease. However, findings of some recent studies (e.g., the PURE study) have contested this association. High saturated fat diets (HFD) have been widely used in rodent research to study the mechanism of insulin resistance and metabolic syndrome. Two separate but somewhat overlapping models-the diacylglycerol (DAG) model and the ceramide model-have emerged to explain the development of insulin resistance. Studies have shown that lipid deposition in tissues such as muscle and liver inhibit insulin signaling via the toxic molecules DAG and ceramide. DAGs activate protein kinase C that inhibit insulin-PI3K-Akt signaling by phosphorylating serine residues on insulin receptor substrate (IRS). Ceramides are sphingolipids with variable acyl group chain length and activate protein phosphatase 2A that dephosphorylates Akt to block insulin signaling. In adipose tissue, obesity leads to infiltration of macrophages that secrete pro-inflammatory cytokines that inhibit insulin signaling by phosphorylating serine residues of IRS proteins. For cardiovascular disease, studies in humans in the 1950s and 1960s linked high saturated fat intake with atherosclerosis and coronary artery disease. More recently, trials involving Mediterranean diet (e.g., PREDIMED study) have indicated that healthy monounsaturated fats are more effective in preventing cardiovascular mortality and coronary artery disease than are low-fat, low-cholesterol diets. Antioxidant and anti-inflammatory effects of Mediterranean diets are potential mediators of these benefits.
10.3390/nu12051505
Sex-Specific Mechanisms of Resistance Vessel Endothelial Dysfunction Induced by Cardiometabolic Risk Factors.
Davel Ana P,Lu Qing,Moss M Elizabeth,Rao Sitara,Anwar Imran J,DuPont Jennifer J,Jaffe Iris Z
Journal of the American Heart Association
BACKGROUND:The incidence of obesity is rising, particularly among women. Microvascular dysfunction is more common with female sex, obesity, and hyperlipidemia and predicts adverse cardiovascular outcomes, but the molecular mechanisms are unclear. Because obesity is associated with mineralocorticoid receptor (MR) activation, we tested the hypothesis that MR in endothelial cells contribute to sex differences in resistance vessel dysfunction in response to cardiometabolic risk factors. METHODS AND RESULTS:Male and female endothelial cell-specific MR knockout mice and MR-intact littermates were randomized to high-fat-diet-induced obesity or obesity with hyperlipidemia induced by adeno-associated virus-based vector targeting transfer of the mutant stable form (DY mutation) of the human (proprotein convertase subtilisin/kexin type 9) gene and compared with control diet. Female but not male mice were sensitive to obesity-induced endothelial dysfunction, whereas endothelial function was impaired in obese hyperlipidemic males and females. In males, obesity or hyperlipidemia decreased the nitric oxide component of vasodilation without altering superoxide production or endothelial nitric oxide synthase expression or phosphorylation. Decreased nitric oxide content in obese males was overcome by enhanced endothelium-derived hyperpolarization-mediated relaxation along with increased SK3 expression. Conversely, in females, endothelium-derived hyperpolarization was significantly impaired by obesity with lower IK1 expression and by hyperlipidemia with lower IK1 and SK3 expression, loss of HO-mediated vasodilation, and increased superoxide production. Endothelial cell-MR deletion prevented endothelial dysfunction induced by risk factors only in females. Rather than restoring endothelium-derived hyperpolarization in females, endothelial cell-MR deletion enhanced nitric oxide and prevented hyperlipidemia-induced oxidative stress. CONCLUSIONS:These data reveal distinct mechanisms driving resistance vessel dysfunction in males versus females and suggest that personalized treatments are needed to prevent the progression of vascular disease in the setting of obesity, depending on both the sex and the metabolic profile of each patient.
10.1161/JAHA.117.007675
Implications of SARS-Cov-2 infection on eNOS and iNOS activity: Consequences for the respiratory and vascular systems.
Nitric oxide : biology and chemistry
Symptoms of COVID-19 range from asymptomatic/mild symptoms to severe illness and death, consequence of an excessive inflammatory process triggered by SARS-CoV-2 infection. The diffuse inflammation leads to endothelium dysfunction in pulmonary blood vessels, uncoupling eNOS activity, lowering NO production, causing pulmonary physiological alterations and coagulopathy. On the other hand, iNOS activity is increased, which may be advantageous for host defense, once NO plays antiviral effects. However, overproduction of NO may be deleterious, generating a pro-inflammatory effect. In this review, we discussed the role of endogenous NO as a protective or deleterious agent of the respiratory and vascular systems, the most affected in COVID-19 patients, focusing on eNOS and iNOS roles. We also reviewed the currently available NO therapies and pointed out possible alternative treatments targeting NO metabolism, which could help mitigate health crises in the present and future CoV's spillovers.
10.1016/j.niox.2021.04.003
Sex Differences in Renal Inflammation and Injury in High-Fat Diet-Fed Dahl Salt-Sensitive Rats.
Fernandes Roxanne,Garver Hannah,Harkema Jack R,Galligan James J,Fink Gregory D,Xu Hui
Hypertension (Dallas, Tex. : 1979)
We examined the impact of sex on high-fat diet (HFD)-induced renal alterations in Dahl salt-sensitive and Sprague Dawley rats. In Dahl rats, HFD (60% kcal from fat for 24-26 weeks starting at weaning) significantly and equally increased blood pressure in males and females when compared with rats fed a control diet (10% kcal from fat). Male Dahl rats on HFD exhibited progressive renal histological injury and moderately increased renal macrophage infiltration at 10 and 24 weeks of feeding when compared with males on control diet. Female Dahl rats had lower grade renal injury and less macrophage infiltration (except at 17 weeks) than males regardless of diet. Male Dahl rats on both diets showed progressively increasing numbers of renal T-cells, a pattern not observed in females. HFD per se did not significantly affect renal T-cell number. Male Dahl rats had lower renal regulatory T-cells cell ratio than females at 24 weeks. Renal macrophage and T-cell infiltrations were highly correlated to final mean arterial pressure levels in males but not in females. Sprague Dawley rats fed HFD were normotensive without significant renal injury/inflammation after 24 weeks of feeding. In summary, HFD feeding fails to increase arterial blood pressure in Sprague Dawley rats but strongly promotes hypertension in both male and female Dahl salt-sensitive rats. Only Dahl males, however, exhibited blood pressure-associated renal inflammation and injury. Maintenance of regulatory T-cells ratio may protect against hypertension-associated renal injury/inflammation but not HFD-induced hypertension.
10.1161/HYPERTENSIONAHA.118.11485
High-fat diet up-regulates caveolin-1 expression in aorta of diet-induced obese but not in diet-resistant rats.
Yang Nianhong,Ying Chenjiang,Xu Mingjia,Zuo Xuezhi,Ye Xiaolei,Liu Liegang,Nara Yasuo,Sun Xiufa
Cardiovascular research
OBJECTIVE:Caveolin-1 (Cav-1) is considered as a negative regulator of endothelial nitric oxide synthase (eNOS) and influences various cardiovascular functions. The objective of the study is to investigate the effects of high-fat diet on vascular Cav-1 expression and eNOS activities. METHODS:Male outbred Sprague-Dawley rats were fed with a high-fat diet for 15 weeks to induce obesity. The diet-induced obese (DIO) rats were then divided into two groups. One group (DIO-LF) was fed a normal diet and another group (DIO-HF) along with diet-resistance (DR) rats were fed a high-fat diet for 8 more weeks. Cav-1 expression was determined using reverse transcription (RT)-PCR, Western blotting, and immunohistochemistry techniques. NOS activities were assessed using Griess reagents. Protein kinase B (PKB/Akt) and eNOS expression and phosphorylation were determined by Western blotting. RESULTS:A high-fat diet up-regulated Cav-1 and down-regulated eNOS expression in aorta of DIO rats, but not in that of DR rats. These effects were reversed in DIO rats after switching to a low-fat diet for 8 weeks. Decreased NOS activities in aortas were observed in DIO rats, but not in DR rats. Phosphorylation of PKB/Akt and eNOS (Ser1177) were enhanced in aortas of DIO rats of both DIO-HF and DIO-LF groups. CONCLUSION:These findings suggest that the decrease of vascular NOS activities in rats fed a high-fat diet were due, at least in part, to the up-regulation of Cav-1 expression.
10.1016/j.cardiores.2007.05.028
Tipping the scales: Are females more at risk for obesity- and high-fat diet-induced hypertension and vascular dysfunction?
Taylor Lia E,Ramirez Lindsey A,Musall Jacqueline B,Sullivan Jennifer C
British journal of pharmacology
Obesity is a common metabolic disorder that has become a widespread epidemic in several countries. Sex and gender disparities in the prevalence of cardiovascular disease (CVD) have been well documented with premenopausal women having a lower incidence of CVD than age-matched men. However, women are more likely than men to suffer from obesity, which can predispose them to a greater risk of CVD. The mechanisms underlying high-fat diet (HFD)- or obesity-induced hypertension are not well defined, although immune system activation and inflammation have been implicated in several studies. Further, the sex of the subject can have a profound influence on the immune response to hypertensive stimuli. Therefore, the purpose of this review is to examine the effects of sex and gender on the role of the immune system in HFD-induced hypertension and vascular dysfunction. LINKED ARTICLES: This article is part of a themed section on The Importance of Sex Differences in Pharmacology Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.21/issuetoc.
10.1111/bph.14783