Impact of Doxorubicin Treatment on the Physiological Functions of White Adipose Tissue.

White adipose tissue (WAT) plays a fundamental role in maintaining energy balance and important endocrine functions. The loss of WAT modifies adipokine secretion and disrupts homeostasis, potentially leading to severe metabolic effects and a reduced quality of life. Doxorubicin is a chemotherapeutic agent used clinically because of its good effectiveness against various types of cancer. However, doxorubicin has deleterious effects in many healthy tissues, including WAT, liver, and skeletal and cardiac muscles. Our objective was to investigate the effects of doxorubicin on white adipocytes through in vivo and in vitro experiments. Doxorubicin reduced the uptake of glucose by retroperitoneal adipocytes and 3T3-L1 cells via the inhibition of AMP-activated protein kinase Thr172 phosphorylation and glucose transporter 4 content. Doxorubicin also reduced the serum level of adiponectin and, to a greater extent, the expression of genes encoding lipogenic (Fas and Acc) and adipogenic factors (Pparg, C/ebpa, and Srebp1c) in retroperitoneal adipose tissue. In addition, doxorubicin inhibited both lipogenesis and lipolysis and reduced the hormone-sensitive lipase and adipose tissue triacylglycerol lipase protein levels. Therefore, our results demonstrate the impact of doxorubicin on WAT. These results are important to understand some side effects observed in patients receiving chemotherapy and should encourage new adjuvant treatments that aim to inhibit these side effects.

Decaffeinated green tea extract rich in epigallocatechin-3-gallate prevents fatty liver disease by increased activities of mitochondrial respiratory chain complexes in diet-induced obesity mice.

Nonalcoholic fatty liver disease has been considered the hepatic manifestation of obesity. It is unclear whether supplementation with green tea extract rich in epigallocatechin-3-gallate (EGCG) influences the activity of mitochondrial respiratory chain complexes and insulin resistance in the liver. EGCG regulated hepatic mitochondrial respiratory chain complexes and was capable of improving lipid metabolism, attenuating insulin resistance in obese mice. Mice were divided into four groups: control diet+water (CW) or EGCG (CE) and hyperlipidic diet+water (HFW) or EGCG (HFE). All animals received water and diets ad libitum for 16 weeks. Placebo groups received water (0.1 ml/day) and EGCG groups (0.1 ml EGCG and 50 mg/kg/day) by gavage. Cytokines concentrations were obtained by ELISA, protein expression through Western blotting and mitochondrial complex enzymatic activity by colorimetric assay of substrate degradation. HFW increased body weight gain, adiposity index, retroperitoneal and mesenteric adipose tissue relative weight, serum glucose, insulin and Homeostasis Model Assessment of Basal Insulin Resistance (HOMA-IR); glucose intolerance was observed in oral glucose tolerance test (OGTT) as well as ectopic fat liver deposition. HFE group decreased body weight gain, retroperitoneal and mesenteric adipose tissue relative weight, HOMA-IR, insulin levels and liver fat accumulation; increased complexes II-III and IV and malate dehydrogenase activities and improvement in glucose uptake in OGTT and insulin sensitivity by increased protein expression of total AKT, IRα and IRS1. We did not find alterations in inflammatory parameters analyzed. EGCG was able to prevent obesity stimulating the mitochondrial complex chain, increasing energy expenditure, particularly from the oxidation of lipid substrates, thereby contributing to the prevention of hepatic steatosis and improved insulin sensitivity.

Green tea extract improves high fat diet-induced hypothalamic inflammation, without affecting the serotoninergic system.

To investigate possible mechanisms of green tea's anti-obesity and anti-diabetic effects in the hypothalamus, the central regulator of metabolism, of mice fed with high-fat diet (HFD), we analyzed proteins of the toll-like receptor 4 (TLR4) pathway and serotoninergic proteins involved in energy homeostasis. Thirty-day-old male Swiss mice were fed with HFD rich in saturated fat and green tea extract (GTE) for 8 weeks. After that, body weight and mass of fat depots were evaluated. Oral glucose tolerance test was performed 3 days prior to euthanasia; serum glucose, insulin and adiponectin were measured in fasted mice. Hypothalamic TLR4 pathway proteins, serotonin receptors 1B and 2C and serotonin transporter were analyzed by Western blotting or enzyme-linked immunosorbent assay. A second set of animals was used to measure food intake in response to fluoxetine, a selective serotonin reuptake inhibitor. Mice fed with HFD had increased body weight and mass of fat depots, impaired oral glucose tolerance, elevated glucose and insulin and decreased adiponectin serum levels. TLR4, IκB-α, nuclear factor κB p50 and interleukin 6 were increased by HFD. Concomitant GTE treatment ameliorated these parameters. The serotoninergic system remained functional after HFD treatment despite a few alterations in protein content of serotonin receptors 1B and 2C and serotonin transporter. In summary, the GTE attenuated the deleterious effects of the HFD investigated in this study, partially due to reduced hypothalamic inflammation.

Hyperleptinemia in obese adolescents deregulates neuropeptides during weight loss.

Leptin has emerged over the past decade as a key hormone not only in energy balance regulation but also in neuroendocrine and inflammatory processes. The aim of the present study was to evaluate whether hyperleptinemia deregulates neuropeptides during weight loss. A total of 86 post-pubertal obese adolescents (with or without hyperleptinemia) participated in one year of interdisciplinary weight loss therapy (clinical, nutritional, psychological and exercise-related). Adipokine and neuropeptide concentrations were measured by ELISA, visceral fat was measured by ultrasound and body composition was measured by pletismography. The hyperleptinemic patients presented a lower alpha-MSH concentration and higher NPY/AgRP ratio while the adiponectin/leptin (A/L) ratio was lower compared with the non-hyperleptinemic group. After therapy, significant improvements in BM, BMI, body fat mass, visceral and subcutaneous fat, HOMA-IR, QUICKI, total cholesterol and triglycerides were observed in both groups. Indeed, we observed significant increases in adiponectin and A/L as well as reductions in leptin and NPY/AgRP ratio in the hyperleptinemic group. In the stepwise multiple linear regression analysis with leptin concentration as the dependent variable, α-MSH and body fat mass (%) were the independent predictors to explain leptin concentration. For the entire group, we found positive correlations between leptinemia and BMI and body fat mass (%) as well as a negative correlation with free fat mass (%) and alpha-MSH. Finally, we verified negative correlations between adiponectin/leptin ratio with total cholesterol and LDL-c, only in hyperleptinemic patients. In conclusion, the hyperleptinemia in obese adolescents deregulates neuropeptides during weight loss.

Exhaustive exercise increases inflammatory response via Toll like receptor-4 and NF-κBp65 pathway in rat adipose tissue.

Cytokines (IL-6, IL-10, and TNF-α) are increased after exhaustive exercise in the retroperitoneal adipose tissue (RPAT) and mesenteric adipose tissue (MEAT). An exhaustive acute exercise protocol induces inflammation in adipose tissue that lasts 6 h after the exercise has ended. It is well-established that this protocol increases circulating plasma levels of non-esterified fatty acids (NEFAs) and lipopolysaccharides (LPS), compounds that are important in stimulating signaling via toll like receptor-4 (TLR-4) in different type cells. In the present study, we investigated the regulation of TLR-4 and DNA-binding of nuclear factor-κBp65 (NF-κBp65) in different depots of adipose tissue in rats after exhaustive exercise. Rats were killed by decapitation immediately (E0 group, n=6), 2 (E2 group, n=6), and 6 h (E6 group, n=6) after the exhaustive exercise, which consisted of running on a treadmill (approximately 70% V(O2max) ) for 50 min and then running at an elevated rate that increased at 1 m/min, until exhaustion. The control group (C group, n=6) was not subjected to exercise. In RPAT, TLR-4, MYD-88, and IkBα increased in the E2 group after exercise. MYD-88 and TRAF6 remained increased in the E6 group in comparison with the control group. DNA-binding of NF-κBp65 was not altered. In MEAT, TLR-4, MYD-88, TRAF6, and DNA-binding of NF-κBp65 were increased only in the E6 group. In conclusion, we have shown that increases in pro-inflammatory cytokines in adipose tissue pads after exhaustive exercise may be mediated via TLR-4 signaling, leading to increases in NF-κBp65 binding to DNA in MEAT.

Fructose alters adiponectin, haptoglobin and angiotensinogen gene expression in 3T3-L1 adipocytes.

Fructose- or sucrose-rich diets can cause insulin resistance and increase the risk of cardiovascular disease. Adipokines are correlated with the development of these diseases in obesity. We hypothesize that fructose and sucrose induce insulin resistance via effects on adipokine gene expression in adipocytes. This study analyzed the effect of fructose or glucose on adiponectin, haptoglobin, and angiotensinogen gene expression in 3T3-L1 adipocytes. Ten days after differentiation, the cells were pretreated with serum- and glucose-free medium. Twenty-four hours later, fructose or glucose (0, 5, 10, or 20 mmol) was added into the medium, and the cells were collected after a further 24 hours. Adiponectin, haptoglobin, and angiotensinogen gene expression were determined. Adiponectin gene expression increased when 10 or 20 mmol glucose was added compared with that observed for the non-hexose-treated cells. A similar effect occurred when 5 mmol fructose was added. Glucose (10 mmol) and fructose (20 mmol) stimulated haptoglobin gene expression in 3T3-L1 adipocytes compared with 0 mmol, with glucose producing a more pronounced effect. Although 20 mmol fructose caused an increase in angiotensinogen gene expression, glucose did not. In conclusion, in this study of 2 hexoses revealed an increase in adiponectin gene expression, suggesting that the effect of a glucose-rich diet on the development of insulin resistance is not related to the effect of these hexoses on adipocyte adiponectin gene expression. However, insulin resistance and cardiovascular disease promoted by fructose-rich diets could be partially related to the effect of fructose on adiponectin and angiotensinogen gene expression.

Exercise training in rats impairs the replenishment of white adipose tissue after partial lipectomy.

The aim of this study was to evaluate the effect of exercise training on the metabolism of rats following the partial removal of fat pads. Three-month-old male Wistar rats were subjected to the partial removal (L) of retroperitoneal white adipose tissue (RET) and epididymal white adipose tissue (EPI), or a sham operation (Sh). Seven days after surgery, both sets of rats were subdivided into exercised (LE or ShE) (swimming 90 min/day, 5 days/week, 6 weeks) and sedentary (LS or ShS) groups. Partial removal of the fat pads increased the lipogenesis rates in both the RET and EPI and decreased the weight and lypolysis rate of the EPI, while the RET weight was not significantly affected by lipectomy. In both lipectomized and sham-operated groups, exercise training caused a reduction in carcass lipid content, food intake, RET and EPI weights, and RET lipogenesis rate. On the other hand, the exercise training increased the percentage of diet-derived lipid accumulation in both tissues, either in sham and lipectomized rats. These results confirmed that regrowth is not uniform and depends on the particular fat pad that is excised. They also demonstrated that exercise training following the partial removal of fat pads modified adipose tissue metabolism, impaired the replenishment of adipose tissue, and decrease body adiposity.

Metabolism and secretory function of white adipose tissue: effect of dietary fat

Approximately 40 percent of the total energy consumed by western populations is represented by lipids, most of them being ingested as triacylglycerols and phospholipids. The focus of this review is to analyze the effect of the type of dietary fat on white adipose tissue metabolism and secretory function, particularly on haptoglobin, TNF-α, plasminogen activator inhibitor-1 and adiponectin secretion. Previous studies have demonstrated that the duration of the exposure to the high-fat feeding, amount of fatty acid present in the diet and the type of fatty acid may or may not have a significant effect on adipose tissue metabolism. However, the long-term or short-term high fat diets, especially rich in saturated fatty acids, probably by activation of toll-like receptors, stimulated the expression of proinflammatory adipokines and inhibited adiponectin expression. Further studies are needed to investigate the cellular mechanisms by which dietary fatty acids affect white adipose tissue metabolism and secretory functions.

Aproximadamente 40 por cento do total de energia consumida pela população ocidental é representada pelos lipídios, a maioria dela sendo ingerida na forma de triglicerídeos e fosfolipídios. O foco desta revisão foi analisar o efeito dos tipos de gordura da dieta sobre o metabolismo e função secretora do tecido adiposo branco, principalmente, sobre a secreção de haptoglobina, TNF-α, inibidor do ativador de plasminogênio-1 e adiponectina. Estudos prévios demonstraram que durante a exposição de dietas hiperlipídicas, a quantidade e o tipo de ácidos graxos presentes na dieta podem ou não ter um efeito significante sobre o metabolismo do tecido adiposo. Entretanto, o tratamento a curto ou longo prazo com dieta hiperlipídica, especialmente rica em ácidos graxos saturados, provavelmente por ativar receptores toll-like, estimula a expressão de adipocinas pró-inflamatórias e inibe a expressão de adiponectina. Estudos adicionais são necessários para investigar os mecanismos celulares pelos quais os ácidos graxos da dieta afetam a função secretória e metabólica do tecido adiposo branco.