Induced Body Weight Gain Research Articles

Grape seed and skin extract reduces pancreas lipotoxicity, oxidative stress and inflammation in high fat diet fed rats.

Obesity is related to an elevated risk of diabetes and the mechanisms whereby fat adversely affects the pancreas are poorly understood. We studied the effect of a high fat diet (HFD) on pancreas steatosis, oxidative stress and inflammation as well as the putative protection afforded by grape seed and skin extract (GSSE). HFD induced body weight gain, without affecting insulinemia, nor glycemia and dropped adiponectemia. HFD also provoked the ectopic deposition of cholesterol and triglyceride, and an oxidative stress characterized by increased lipoperoxidation and carbonylation, inhibition of antioxidant enzyme activities such as CAT, GPx and SOD, depletion of zinc and a concomitant increase in calcium and H2O2. HFD induced pro-inflammatory chemokines mRNA as RANTES and MCP1 as well as cytokines expression as TNFα, IL6 and IL1β. Importantly GSSE counteracted all the deleterious effects of HFD on pancreas in vivo i-e lipotoxicity, oxidative stress and inflammation. In conclusion, GSSE could find potential applications in fat-induced pancreas lipotoxicity and dysfunction.

효소 처리된 Isoquercitrin이 고지방식이에 의해 비만이 유도된 마우스의 체중감소에 미치는 영향

Enzymatically modified isoquercitrin (EMIQ) is a mixture of quercetin glycodsides consisting of isoquercitrin and its α-glucosylated derivatives containing one to seven additional linear glucose moieties. The aim of this study was to assess whether or not EMIQ attenuates high-fat diet (HFD)-induced body weight gain and changes in plasma indices of obesity in mice. Male C57BL/6N mice were fed chow diet, HFD, and HFD containing 1.2% EMIQ for 10 weeks. EMIQ significantly (P<0.05) reduced body weight gain (-21%), total visceral fat-pad weights(-31%), and plasma levels of triglycerides (-17%), total cholesterol (-19%), and free fatty acids (-26%) in HFD-fed mice. EMIQ significantly increased protein kinase A (PKA) expression in the epididymal adipose tissue of HFD-fed mice. Expression of adipogenesis-related genes significantly decreased, whereas expression of fatty acid oxidation-related and thermogenesis-related genes increased in epididymal adipose tissue of EMIQ-fed mice compared with HFD-fed mice. These results suggest that the protective effects of EMIQ against HFD-induced adiposity in mice appear to be associated with PKA-mediated signaling cascades involved in adipogenesis, fatty acid oxidation, and thermogenesis in adipose tissue.

Delayed Intervention With Pyridoxamine Improves Metabolic Function and Prevents Adipose Tissue Inflammation and Insulin Resistance in High-Fat Diet-Induced Obese Mice.

Obesity is associated with an increased risk for the development of type 2 diabetes and vascular complications. Advanced glycation end products are increased in adipose tissue and have been associated with insulin resistance, vascular dysfunction, and inflammation of adipose tissue. Here, we report that delayed intervention with pyridoxamine (PM), a vitamin B6 analog that has been identified as an antiglycating agent, protected against high-fat diet (HFD)-induced body weight gain, hyperglycemia, and hypercholesterolemia, compared with mice that were not treated. In both HFD-induced and db/db obese mice, impaired glucose metabolism and insulin resistance were prevented by PM supplementation. PM inhibited the expansion of adipose tissue and adipocyte hypertrophy in mice. In addition, adipogenesis of murine 3T3-L1 and human Simpson-Golabi-Behmel Syndrome preadipocytes was dose- and time-dependently reduced by PM, as demonstrated by Oil Red O staining and reduced expression of adipogenic differentiation genes. No ectopic fat deposition was found in the liver of HFD mice. The high expression of proinflammatory genes in visceral adipose tissue of the HFD group was significantly attenuated by PM. Treatment with PM partially prevented HFD-induced mild vascular dysfunction. Altogether, these findings highlight the potential of PM to serve as an intervention strategy in obesity.

Chronic vitamin A-enriched diet feeding induces body weight gain and adiposity in lean and glucose-intolerant obese rats of WNIN/GR-Ob strain.

What is the central question of this study? Previously, we reported that chronic feeding of a vitaminA-enriched diet to euglycaemic obese rats (WNIN/Ob) ameliorated obesity. Does this diet exert similar effects even with a different genetic background, i.e. obese rats of the WNIN/GR-Ob strain with impaired glucose tolerance? What is the main finding and its importance? VitaminA-enriched diet aggravated weight gain and adiposity/obesity in both lean and glucose-intolerant obese rats of the WNIN/GR-Ob strain. Therefore, the role of genetic factors and their regulation by nutrients in determining health and disease conditions assumes greater significance in experimental and clinical research. Vitamin A and its metabolites are key regulators of the development of adipose tissue and its associated metabolic complications. Here, we tested, in a glucose-intolerant obese rat model (the WNIN/GR-Ob stain), whether feeding a vitaminA-enriched diet alters adiposity and its associated changes. For this purpose, 30-week-old male lean and obese rats were divided into two groups and received either stock diet or vitaminA-enriched diet [2.6 or 129mg vitaminA(kg diet)(-1) , respectively] for 14weeks. At the end, feeding of the vitaminA-enriched diet resulted in increased body weight gain/obesity and retroperitoneal white adipose tissue (RPWAT) in both lean and obese rats of the WNIN/GR-Ob strain, when compared with their respective control animals receiving stock diet, without affecting food intake. An improvement in hypertriglyceridaemia and circulatory non-esterified fatty acid levels and unaltered hepatic fatty acid oxidative and triglyceride secretory pathway proteins with vitamin A-enriched diet feeding are suggestive of enhanced hepatic clearance of circulatory lipids, resulting in increased hepatic triglyceride accumulation. Transcriptional analysis of RPWAT showed that feeding the vitaminA-enriched diet augmented the expression of adipogenic/adipose tissue-specific genes; peroxisome proliferator-activated receptor-γ, stearoyl CoA desaturase1, retinol saturase, leptin and lipoprotein lipase and vitaminA metabolic pathway genes; retinoic acid receptors, retinoid X receptors and cytochrome P450 26B1. Besides, RPWAT-lipoprotein lipase-mediated clearance of triglyceride could also have contributed to increased adiposity and improved hypertriglyceridaemia. In conclusion, chronic feeding of vitamin A-enriched diet induces weight gain and adiposity in both lean and obese rats of the WNIN/GR-Ob strain, possibly through transcriptional regulation of key adipogenic pathway genes of RPWAT, but improves dyslipidaemia.

Medium-chain triglyceride ameliorates insulin resistance and inflammation in high fat diet-induced obese mice.

The aim of the present study was to investigate the in vivo effects of dietary medium-chain triglyceride (MCT) on inflammation and insulin resistance as well as the underlying potential molecular mechanisms in high fat diet-induced obese mice. Male C57BL/6J mice (n = 24) were fed one of the following three diets for a period of 12 weeks: (1) a modified AIN-76 diet with 5 % corn oil (normal diet); (2) a high-fat control diet (17 % w/w lard and 3 % w/w corn oil, HFC); (3) an isocaloric high-fat diet supplemented with MCT (17 % w/w MCT and 3 % w/w corn oil, HF-MCT). Glucose metabolism was evaluated by fasting blood glucose levels and intraperitoneal glucose tolerance test. Insulin sensitivity was evaluated by fasting serum insulin levels and the index of homeostasis model assessment-insulin resistance. The levels of serum interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor-α were measured by ELISA, and hepatic activation of nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways was determined using western blot analysis. Compared to HFC diet, consumption of HF-MCT did not induce body weight gain and white adipose tissue accumulation in mice. HFC-induced increases in serum fasting glucose and insulin levels as well as glucose intolerance were prevented by HF-MCT diet. Meanwhile, HF-MCT resulted in significantly lower serum IL-6 level and higher IL-10 level, and lower expression levels of inducible nitric oxide synthase and cyclooxygenase-2 protein in liver tissues when compared to HFC. In addition, HF-MCT attenuated HFC-triggered hepatic activation of NF-κB and p38 MAPK. Our study demonstrated that MCT was efficacious in suppressing body fat accumulation, insulin resistance, inflammatory response, and NF-κB and p38 MAPK activation in high fat diet-fed mice. These data suggest that MCT may exert beneficial effects against high fat diet-induced insulin resistance and inflammation.

Keeping gut lining at bay: impact of emulsifiers

Obesity is associated with altered gut microbiota and low-grade inflammation. Both dietary habits and food composition contribute to the onset of such diseases. Emulsifiers, compounds commonly used in a variety of foods, were shown to induce body weight gain, low-grade inflammation and metabolic disorders. These dietary compounds promote gut microbiota alteration and gut barrier dysfunction leading to negative metabolic alterations.

Hepatoprotective and Renoprotective Effects of Lavender (Lavandula stoechas L.) Essential Oils Against Malathion-Induced Oxidative Stress in Young Male Mice.

We aimed in the present study to investigate the hepato- and nephroprotective effects of Lavandula stoechas essential oils (LSEO) against malathion-induced oxidative stress in young male mice as well as the possible mechanism implicated in such protection. Animals were divided into eight groups of 12 each: Control, malathion (200 mg/kg b.w.); Various doses of LSEO (10, 30, and 50 mg/kg b.w.), malathion+various doses of LSEO. Malathion and LSEO were daily per orally (p.o.) administered by intragastric gavage during 30 days. We initially found that malathion treatment induced body weight gain decrease as well as a clear nephro- and hepatotoxicity as assessed by significant relative liver and kidney weight increase and related hemodynamic parameters deregulation. Malathion exposure of mice also induced a considerable perturbation of metabolic parameters. On the other hand, we showed that malathion administration was accompanied by an oxidative stress status assessed by an increase of malondialdehyde (MDA) and hydrogen peroxide (H2O2) levels as well as a depletion of sulfhydril group content (-SH) and antioxidant enzyme activities such as catalase (CAT) and glutathione peroxidase (GPx), total superoxide dismutase (SOD), Cu/Zn-SOD, Mn-SOD, and Fe-SOD in the kidney and liver. More importantly, LSEO treatment abolished all malathion-induced body gain loss, liver and kidney relative weight increase, hemodynamic and metabolic disorders, as well as hepatic and renal oxidative stress. In conclusion, our data suggest that LSEO exerted potential hepato- and nephroprotective effects against malathion-induced oxidative stress in mice. The beneficial effect of LSEO might be related, in part, to its antioxidant properties.

Oleuropein attenuates visceral adiposity in high-fat diet-induced obese mice through the modulation of WNT10b- and galanin-mediated signalings.

The aim of the present study was to investigate the antiobesity effect of oleuropein on high-fat diet (HFD) induced body weight gain and visceral adiposity in mice, and to explore the underlying mechanisms involved. C57BL/6N mice were fed with a normal diet, HFD (40% fat of total energy), and HFD-supplemented with 0.03% oleuropein for 10 wk. Oleuropein significantly reduced HFD-induced body weight gain and visceral adiposity. Oleuropein also significantly reversed the HFD-induced elevations of adipogenic related gene expression involved in WNT10b- and galanin-mediated signalings in adipose tissue of mice. Consistent with in vivo findings, oleuropein dose-dependently suppressed lipid accumulation in 3T3-L1 cells during preadipocyte differentiation. Additionally, exposure of the 3T3-L1 preadipocytes to oleuropein resulted in a marked attenuation of the secreted frizzled-related protein 2 (WNT inhibitor) or galnon (galanin receptor agonist) induced cellular lipid accumulation. This study demonstrated the oleuropein-reduced body weight gain and visceral adiposity in HFD-fed mice. The protective effect of oleuropein against HFD-induced adiposity in mice appeared to be mediated through the upregulation of genes involved in WNT10b-mediated signaling and downregulation of genes involved in galanin-mediated signaling cascades.

Quercetin decreases high-fat diet induced body weight gain and accumulation of hepatic and circulating lipids in mice.

Dietary flavonoids may protect against cardiovascular diseases (CVD). Increased circulating lipid levels and hepatic lipid accumulation are known risk factors for CVD. The aim of this study was to investigate the effects and underlying molecular mechanisms of the flavonoid quercetin on hepatic lipid metabolism in mice with high-fat diet induced body weight gain and hepatic lipid accumulation. Adult male mice received a 40 energy% high-fat diet without or with supplementation of 0.33% (w/w) quercetin for 12weeks. Body weight gain was 29% lower in quercetin fed mice (p<0.01), while the energy intake was not significantly different. Quercetin supplementation lowered hepatic lipid accumulation to 29% of the amount present in the control mice (p<0.01). (1)H nuclear magnetic resonance serum lipid profiling revealed that the supplementation significantly lowered serum lipid levels. Global gene expression profiling of liver showed that cytochrome P450 2b (Cyp2b) genes, key target genes of the transcription factor constitutive androstane receptor (Car; official symbol Nr1i3), were downregulated. Quercetin decreased high-fat diet induced body weight gain, hepatic lipid accumulation and serum lipid levels. This was accompanied by regulation of cytochrome P450 2b genes in liver, which are possibly under transcriptional control of CAR. The quercetin effects are likely dependent on the fat content of the diet.

Oxidative stress and obesity: the chicken or the egg?

Over the past 30 years much research has focused on elucidating mechanisms linked to progression of obesity and its cardiovascular comorbidities. As the central dogma regarding the pathophysiology of obesity unfolds, it is evident that the expansion of visceral adipose tissue caused by overconsumption of nutrients plays a central role. As visceral fat stores expand, adipocytes generate increasing levels of reactive oxygen species (ROS) that incite increased expression and secretion of inflammatory adipokines (1–3). Oxidative stress leads to insulin resistance within adipose tissue as well as in peripheral tissues. Insulin resistance is one of the hallmarks of obesity and accounts for many of its comorbidities, including hypertension (4). Accumulation of oxidative stress in adipose tissue is one of the early events in the development of metabolic syndrome in obesity (5). On the other hand, weight loss by calorie restriction and/or exercise can ameliorate the state of oxidative stress (6). Nonetheless, a cause and effect relationship between oxidative stress and obesity is not well understood. NADPH oxidase is a major contributor to oxidative stress in many tissues, including adipose tissue and the vasculature (5,7,8). Conversely, factors causing oxidative stress, such as angiotensin II, that induce insulin resistance do not necessarily induce body weight gain (9). Therefore, whether oxidative stress, per se, leads to weight gain is an important gap in our understanding of the pathophysiology of obesity. In this issue, Youn et al. (10 …

Effects of afala and antiestrogen ICI 182,780 in the model of hormone-dependent prostate inflammation.

In the hormone-dependent prostate inflammation model induced by implantation of slow-releasing pellets (50 mg testosterone and 5 mg estradiol) to Noble male rats, intragastric administration of Afala at a dose of 7.5 ml/kg for 18 weeks reduced the number of inflamed prostatic acini. The effect of afala was comparable with that of antiestrogen ICI 182,780 (3 mg/kg subcutaneously twice a week for 18 weeks). Prolonged treatment with hormones in high doses induced severe inflammation of the prostate tissue, which was not terminated by the test preparations. As differentiated from the antiestrogen ICI 182,780, afala did not induce body weight gain and decrease in pituitary weight in experimental animals in comparison with the control group.

Preventive effects of the methanol soluble fraction of Millettia macrophylla Benth (Fabaceae) on an osteoporosis-like model of ovariectomized Wistar rats

Millettia macrophylla Benth is a Cameroonian medicinal plant traditionally used to alleviate menopause-related problems. The methanol soluble fraction of this plant was shown to exhibit estrogenic effects in vitro in Human Embryonic kidney cells, and in vivo on ovariectomized rat following the classical uterotrophic assay. Since estrogens have been involved in bone remodeling process, the present study then aimed at evaluating bone loss preventive effects of the methanol soluble fraction of Millettia macrophylla (MM-met) in ovariectomized rat model. Twenty-five healthy Wistar female rats (3-month-old) were randomly assigned to a sham-operated group and to four treated ovariectomized (OVX) groups. Treatments lasted 8 weeks and animals were sacrificed. The uterus, the femoral and the tibia bones of each animal were collected, weighed and fixed in 10% formalin for histological analysis. Results showed that ovariectomy decreased uterine wet weight (p<0.01), induced body weight gain (p<0.01), decreased both femoral and tibia bone density and mineral content and increased alkaline phosphatase activity (p<0.05). E2V and MM-met treatments in general prevented bone mass loss and/or bone density loss. At all tested doses, MM-met induced a significant decrease of alkaline phosphatase activity (p<0.05). As observed with E2V, MM-met also induced a significant protective effect on bone, and this was indicated by an abundance of bone marrow in an almost intact trabecular network. The overall results show that the methanol soluble fraction of Millettia macrophylla may prevent ovariectomy-induced bone mass loss and deterioration of the trabecular microarchitecture.

Bile acid sequestrants activate novel signaling pathways in the kidney and prevent obesity‐induced renal disease (767.10)

Bile acid sequestrants (BAS) are orally administered nonabsorbable polymers that decrease serum cholesterol and serum glucose in patients and animal models with type 2 diabetes mellitus. The effects of BAS on renal dysfunction in obesity and insulin resistance or type 2 diabetes mellitus have not been studied. Our goal was to evaluate the effect of BAS on metabolic and renal parameters in diet induced obesity. Our studies were performed in C57BL/6J male mice fed a control low fat (LF) diet (10 kcal% fat) or high fat (HF) diet (60 kcal% fat). The diets were supplemented with a) no addition or b) 2% sevelamer a BAS. Treatment with BAS prevented HF diet induced body weight gain, improved fasting blood glucose and glucose tolerance, and prevented the increases in serum cholesterol as well as insulin and leptin levels in HF mice. BAS prevented the increase in urine albumin excretion and decreased the PAS staining in the kidney of HF mice. Treatment with BAS decreased the renal lipid accumulation as shown by oil red O staining. HF diet induced upregulation of profibrotic genes (TGF‐β, CTGF, and PAI‐1) and proinflammatory genes (MCP‐1, TLR2, and TLR4) in the kidney which were decreased by treatment with BAS. In addition BAS induced downregulation of extracellular matrix protein fibronectin and macrophage marker CD68 expression in the kidney. The beneficial effects of BAS were also associated with decreases in renal gluconeogenic gene expression (PEPCK and G6Pase) and renal glucose transporter (SGLT2). Treatment with BAS also and most notably increased renal expression of Nrf1, SIRT1, PGC‐1a,SIRT3, ERRa, that mediate mitochondrial biogenesis, MCAD and LCAD, that mediate fatty acid oxidation, and Nrf2, HO‐1, and SOD, that mediate anti‐oxidative stress. In summary, our study showed a novel renoprotective role for bile acid sequestrant treatment in mice with diet induced obesity, insulin and leptin resistance.Grant Funding Source: NIH, VA, Genzyme, Daiichi Sankyo

Effect of Exercise on Photoperiod-Regulated Hypothalamic Gene Expression and Peripheral Hormones in the Seasonal Dwarf Hamster Phodopus sungorus

The Siberian hamster (Phodopus sungorus) is a seasonal mammal responding to the annual cycle in photoperiod with anticipatory physiological adaptations. This includes a reduction in food intake and body weight during the autumn in anticipation of seasonally reduced food availability. In the laboratory, short-day induction of body weight loss can be reversed or prevented by voluntary exercise undertaken when a running wheel is introduced into the home cage. The mechanism by which exercise prevents or reverses body weight reduction is unknown, but one hypothesis is a reversal of short-day photoperiod induced gene expression changes in the hypothalamus that underpin body weight regulation. Alternatively, we postulate an exercise-related anabolic effect involving the growth hormone axis. To test these hypotheses we established photoperiod-running wheel experiments of 8 to 16 weeks duration assessing body weight, food intake, organ mass, lean and fat mass by magnetic resonance, circulating hormones FGF21 and insulin and hypothalamic gene expression. In response to running wheel activity, short-day housed hamsters increased body weight. Compared to short-day housed sedentary hamsters the body weight increase was accompanied by higher food intake, maintenance of tissue mass of key organs such as the liver, maintenance of lean and fat mass and hormonal profiles indicative of long day housed hamsters but there was no overall reversal of hypothalamic gene expression regulated by photoperiod. Therefore the mechanism by which activity induces body weight gain is likely to act largely independently of photoperiod regulated gene expression in the hypothalamus.

Estrogen suppresses adipogenesis by inhibiting S100A16 expression

The aim of this study is to determine the effects of E2 on metabolic syndrome and the molecular mechanisms involving S100A16. Ovariectomized (OVX) rat models and mouse embryonic fibroblasts cell models were used. E2 loss in OVX rats induced body weight gain and central abdominal fat accumulation, which were ameliorated by E2 treatment under chow and high-fat diet (HFD) conditions. E2 decreased the expression of the adipocyte marker genes PPAR γ, aP2, C/EBP α, and S100A16. E2 inhibited adipogenesis. Overexpression of S100A16 reversed the E2-induced adipogenesis effect. A luciferase assay showed that E2 inhibited the expression of S100A16. E2 treatment decreased body weight gain and central abdominal fat accumulation under both chow and HFD conditions. Also, E2 suppressed adipogenesis by inhibiting S100A16 expression.

Protein tyrosine phosphatase 1B and insulin resistance: role of endoplasmic reticulum stress/reactive oxygen species/nuclear factor kappa B axis.

Obesity-induced endoplasmic reticulum (ER) stress has been proposed as an important pathway in the development of insulin resistance. Protein-tyrosine phosphatase 1B (PTP1B) is a negative regulator of insulin signaling and is tethered to the ER-membrane. The aim of the study was to determine the mechanisms involved in the crosstalk between ER-stress and PTP1B. PTP1B whole body knockout and C57BL/6J mice were subjected to a high-fat or normal chow-diet for 20 weeks. High-fat diet feeding induced body weight gain, increased adiposity, systemic glucose intolerance, and hepatic steatosis were attenuated by PTP1B deletion. High-fat diet- fed PTP1B knockout mice also exhibited improved glucose uptake measured using [3H]-2-deoxy-glucose incorporation assay and Akt phosphorylation in the skeletal muscle tissue, compared to their wild-type control mice which received similar diet. High-fat diet-induced upregulation of glucose-regulated protein-78, phosphorylation of eukaryotic initiation factor 2α and c-Jun NH2-terminal kinase-2 were significantly attenuated in the PTP1B knockout mice. Mice lacking PTP1B showed decreased expression of the autophagy related protein p62 and the unfolded protein response adaptor protein NCK1 (non-catalytic region of tyrosine kinase). Treatment of C2C12 myotubes with the ER-stressor tunicamycin resulted in the accumulation of reactive oxygen species (ROS), leading to the activation of protein expression of PTP1B. Furthermore, tunicamycin-induced ROS production activated nuclear translocation of NFκB p65 and was required for ER stress-mediated expression of PTP1B. Our data suggest that PTP1B is induced by ER stress via the activation of the ROS-NFκB axis which is causes unfolded protein response and mediates insulin resistance in the skeletal muscle under obese condition.

Start of insulin therapy in patients with type 2 diabetes mellitus promotes the influx of macrophages into subcutaneous adipose tissue

Insulin therapy in patients with type 2 diabetes mellitus is accompanied by weight gain characterised by an increase in abdominal fat mass. The expansion of adipose tissue mass is generally paralleled by profound morphological and inflammatory changes. We hypothesised that the insulin-associated increase in fat mass would also result in changes in the morphology of human subcutaneous adipose tissue and in increased inflammation, especially when weight gain was excessive. We investigated the effects of weight gain on adipocyte size, macrophage influx, and mRNA expression and protein levels of key inflammatory markers within the adipose tissue in patients with type 2 diabetes mellitus before and 6 months after starting insulin therapy. As expected, insulin therapy significantly increased body weight. At the level of the subcutaneous adipose tissue, insulin treatment led to an influx of macrophages. When comparing patients gaining no or little weight with patients gaining >4% body weight after 6 months of insulin therapy, both subgroups displayed an increase in macrophage influx. However, individuals who had gained weight had higher protein levels of monocyte chemoattractant protein-1, TNF-α and IL-1β after 6 months of insulin therapy compared with those who had not gained weight. We conclude that insulin therapy in patients with type 2 diabetes mellitus improved glycaemic control but also induced body weight gain and an influx of macrophages into the subcutaneous adipose tissue. In patients characterised by a pronounced insulin-associated weight gain, the influx of macrophages into the adipose tissue was accompanied by a more pronounced inflammatory status. ClinicalTrials.gov: NCT00781495. The study was funded by European Foundation for the Study of Diabetes and the Dutch Diabetes Research Foundation.

3,5-di-iodothyronine stimulates tilapia growth through an alternate isoform of thyroid hormone receptor β1

Recent studies in our laboratory have shown that in some teleosts, 3,5-di-iodothyronine (T2 or 3,5-T2) is as bioactive as 3,5,3'-tri-iodothyronine (T3) and that its effects are in part mediated by a TRβ1 (THRB) isoform that contains a 9-amino acid insert in its ligand-binding domain (long TRβ1 (L-TRβ1)), whereas T3 binds preferentially to a short TRβ1 (S-TRβ1) isoform that lacks this insert. To further understand the functional relevance of T2 bioactivity and its mechanism of action, we used in vivo and ex vivo (organotypic liver cultures) approaches and analyzed whether T3 and T2 differentially regulate the S-TRβ1 and L-TRβ1s during a physiological demand such as growth. In vivo, T3 and T2 treatment induced body weight gain in tilapia. The expression of L-TRβ1 and S-TRβ1 was specifically regulated by T2 and T3 respectively both in vivo and ex vivo. The TR antagonist 1-850 effectively blocked thyroid hormone-dependent gene expression; however, T3 or T2 reversed 1-850 effects only on S-TRβ1 or L-TRβ1 expression, respectively. Together, our results support the notion that both T3 and T2 participate in the growth process; however, their effects are mediated by different, specific TRβ1 isoforms.

Promising role of ferulic acid, atorvastatin and their combination in ameliorating high fat diet-induced stress in mice

AimsThe present study evaluated a comparative and combined hepatoprotective effect of atorvastatin (AS) and ferulic acid (F) against high fat diet (HFD) induced oxidative stress in terms of hyperlipidemia, anti-oxidative status, lipid peroxidation and inflammation. Main methodsMale Swiss albino mice were given a diet containing high fat (H) (23.9% wt/wt), supplemented with AS (10mg/kg) or F (100mg/kg) and both (10 and 100mg/kg) for 8weeks. The control mice (C) were fed with normal diet. Key findingsThe H mice exhibited increased body weight; hyperlipidemia; serum level of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6); hepatic lipid profile; lipid accumulation; reactive oxygen species (ROS) of hepatocytes, lipid peroxidation and liver antioxidant capacity was decreased. Immunofluorescent and Western blot assay revealed activation of nuclear factor kappa B (NF-κB) signaling pathway. The addition of F or AS and both in the diet significantly counteracted HFD induced body weight gain; hyperlipidemia; TNF-α, IL-6; hepatic lipid profile; fatty infiltration; NF-κB signaling pathway; ROS; lipid peroxidation and moreover elevated levels of hepatic antioxidant enzymes activity were observed. SignificanceSimultaneous treatment with AS, F and their combination protected against HFD induced weight gain and oxidative stress. The protection may be attributed to the hypolipidemic and free radical scavenging activity of AS or F and their combination. This study illustrates that AS and F have relatively similar hypolipidemic, antioxidative, anti-inflammatory actions and the AS+F combination along with HFD has shown outstanding effects as compared to other treated groups.

Imbalance between Neutrophil Elastase and its Inhibitor α1-Antitrypsin in Obesity Alters Insulin Sensitivity, Inflammation, and Energy Expenditure

The molecular mechanisms involved in the development of obesity and related complications remain unclear. Here, we report that obese mice and human subjects have increased activity of neutrophil elastase (NE) and decreased serum levels of the NE inhibitor α1-antitrypsin (A1AT, SerpinA1). NE null (Ela2(-/-)) mice and A1AT transgenic mice were resistant to high-fat diet (HFD)-induced body weight gain, insulin resistance, inflammation, and fatty liver. NE inhibitor GW311616A reversed insulin resistance and body weight gain in HFD-fed mice. Ela2(-/-) mice also augmented circulating high molecular weight (HMW) adiponectin levels, phosphorylation of AMP-activated protein kinase (AMPK), and fatty acid oxidation (FAO) in the liver and brown adipose tissue (BAT) and uncoupling protein (UCP1) levels in the BAT. These data suggest that the A1AT-NE system regulates AMPK signaling, FAO, and energy expenditure. The imbalance between A1AT and NE contributes to the development of obesity and related inflammation, insulin resistance, and liver steatosis.