Higher Intra-Abdominal Visceral Adipose Tissue Mass Is Associated With Lower Rates of Clinical and Endoscopic Remission in Patients With Inflammatory Bowel Diseases Initiating Biologic Therapy: Results of the Constellation Study.

BACKGROUND & AIMS: We sought to assess the association between intra-abdominal visceral adipose tissue (IA-VAT) and response to 3 different biologic drugs in patients with inflammatory bowel disease (IBD) and to investigate its effects on inflammatory cytokine expression, pharmacokinetics, and intestinal microbiota. METHODS: We prospectively enrolled subjects with active IBD initiating infliximab, vedolizumab, or ustekinumab and a healthy control group. Baseline body composition (including IA-VAT as percent of total body mass [IA-VAT%]) was measured using GE iDXA scan. Primary outcome was corticosteroid- free deep remission at weeks 14-16, defined as Harvey Bradshaw Index <5 for Crohn's disease and partial Mayo score <2 for ulcerative colitis, with a normal C-reactive protein and fecal calprotectin. Secondary outcomes were corticosteroid-free deep remission and endoscopic remission (Endoscopic Mayo Score ≤1 in ulcerative colitis or Simple Endoscopic Score for Crohn's disease ≤2) at weeks 30-46. RESULTS: A total of 141 patients with IBD and 51 healthy controls were included. No differences in body composition parameters were seen between the IBD and healthy control cohorts. Patients with higher IA-VAT% were less likely to achieve corticosteroid-free deep remission (P < .001) or endoscopic remission (P = .02) vs those with lower IA-VAT%. Furthermore, nonresponders with high IA-VAT% had significantly higher serum interleukin-6 and tumor necrosis factor at baseline compared with responders and patients with low IA-VAT%. Drug pharmacokinetic properties and microbiota diversity were similar when comparing high and low IA-VAT% groups. CONCLUSIONS: Higher IA-VAT% was independently associated with worse outcomes. This association could be driven at least partially by discrete differences in inflammatory cytokine expression.

Adipose tissue radiodensity and mortality among patients with nonmetastatic breast cancer.

BACKGROUND & AIMS: Computed tomography (CT) scans can measure quantity and distribution of adipose tissue, which are associated with breast cancer prognosis. As a novel prognostic marker, radiodensity of adipose tissue has been examined in multiple cancer types, but never in breast cancer. Lower density indicates larger adipocytes with greater lipid content, whereas higher density can reflect inflammation, fibrosis, vascularity, or even metabolic changes; and both may impact breast cancer prognosis. METHODS: We included 2868 nonmetastatic patients with breast cancer diagnosed between January 2005 and December 2013 at Kaiser Permanente Northern California, an integrated healthcare system. From CT scans at diagnosis, we assessed the radiodensity of subcutaneous (SAT) and visceral adipose tissue (VAT) at the third lumbar vertebra and categorized their radiodensity into three levels: low (<1 standard deviation [SD] below the mean), middle (mean ± 1 SD), and high (>1 SD above the mean). Using multivariable Cox proportional hazards regression with adjustment for clinicopathological characteristics including body mass index, we calculated hazard ratios (HRs [95% confidence intervals]) for the associations of adipose tissue radiodensity with overall mortality and breast-cancer-specific mortality. RESULTS: Median age at diagnosis of breast cancer was 56.0 years, most (63.3%) were non-Hispanic White and nearly half (45.6%) were stage II. Compared to middle SAT radiodensity, high SAT radiodensity was significantly associated with increased risk of overall mortality (HR: 1.45 [1.15-1.81]), non-significantly with breast-cancer-specific mortality (HR: 1.32 [0.95-1.84]). Neither low SAT radiodensity nor high or low VAT radiodensity was significantly associated with overall or breast-cancer-specific mortality. CONCLUSIONS: High radiodensity of SAT at diagnosis of nonmetastatic breast cancer was associated with increased risk of overall mortality, independent of adiposity and other prognostic factors. Considering both radiodensity and quantity of adipose tissue at different locations could deepen understanding of the role of adiposity in breast cancer survival.

Visceral adipose tissue imparts peripheral macrophage influx into the hypothalamus.

BACKGROUND: Obesity is characterized by a systemic inflammation and hypothalamic neuroinflammation. Systemic inflammation is caused by macrophages that infiltrate obese adipose tissues. We previously demonstrated that high-fat diet (HFD)-fed male mice exhibited peripheral macrophage infiltration into the hypothalamus, in addition to activation of resident microglia. Since this infiltration contributes to neuroinflammation and neuronal impairment, herein we characterize the phenotype and origin of these hypothalamic macrophages in HFD mice. METHODS: C57BL/6J mice were fed HFD (60% kcal from fat) or control diet with matching sucrose levels, for 12-16 weeks. Males and females were analyzed separately to determine sex-specific responses to HFD. Differences in hypothalamic gene expression in HFD-fed male and female mice, compared to their lean controls, in two different areas of the hypothalamus, were determined using the NanoString neuroinflammation panel. Phenotypic changes in macrophages that infiltrated the hypothalamus in HFD-fed mice were determined by analyzing cell surface markers using flow cytometry and compared to changes in macrophages from the adipose tissue and peritoneal cavity. Adipose tissue transplantation was performed to determine the source of hypothalamic macrophages. RESULTS: We determined that hypothalamic gene expression profiles demonstrate sex-specific and region-specific diet-induced changes. Sex-specific changes included larger changes in males, while region-specific changes included larger changes in the area surrounding the median eminence. Several genes were identified that may provide partial protection to female mice. We also identified diet-induced changes in macrophage migration into the hypothalamus, adipose tissue, and peritoneal cavity, specifically in males. Further, we determined that hypothalamus-infiltrating macrophages express pro-inflammatory markers and markers of metabolically activated macrophages that were identical to markers of adipose tissue macrophages in HFD-fed mice. Employing adipose tissue transplant, we demonstrate that hypothalamic macrophages can originate from the visceral adipose tissue. CONCLUSION: HFD-fed males experience higher neuroinflammation than females, likely because they accumulate more visceral fat, which provides a source of pro-inflammatory macrophages that migrate to other tissues, including the hypothalamus. Our findings may explain the male bias for neuroinflammation and the metabolic syndrome. Together, our results demonstrate a new connection between the adipose tissue and the hypothalamus in obesity that contributes to neuroinflammation and hypothalamic pathologies.

Chia (Salvia hispanica)-supplemented diet ameliorates non-alcoholic fatty liver disease and its metabolic abnormalities in humans.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a public health problem lacking an approved pharmacological treatment. Omega-3 fatty acids have shown to reverse NAFLD. Chia is a seed rich in α-linolenic acid (ALA), antioxidants, and fiber; therefore, it could be useful to treat NAFLD. METHODS: In a single arm experimental design study, the effect of 25 g/day of milled chia was assessed in 25 patients with NAFLD. After two weeks of dietary stabilization (basal condition) and eight weeks of a chia-supplemented isocaloric diet, liver:spleen attenuation index and visceral abdominal fat (VAF) were measured by computed tomography. Lipids, lipoproteins, free fatty acids (FFA), and ALA plasma concentrations were also determined. RESULTS: Dietary chia supplementation induced an increase in plasma ALA concentration (75%) and dietary fiber (55%) consumption. After chia supplementation, VAF (9%), body weight (1.4%), total cholesterol (2.5%), non-high density lipoprotein cholesterol (3.2%), and circulating FFA (8%) decreased. Furthermore, NAFLD regressed in 52% of the treated patients (P < 0.05 for all). CONCLUSIONS: The results of the present study show that 25 g/day of milled chia ameliorates NAFLD. Chia is an accessible vegetal source of omega-3 fatty acids, antioxidants, and fiber, which could have the potential to prevent metabolic abnormalities in NAFLD patients. Considering that there is no pharmacological treatment approved for NAFLD, the findings of the present study suggest that a chia-supplemented diet could be an innovative alternative to control this disease. RETROSPECTIVELY REGISTERED: https://clinicaltrials.gov/show/NCT03942822.

Fish oil supplementation to a high-fat diet improves both intestinal health and the systemic obese phenotype.

Impaired intestinal health characterized by a dysbiotic microbial community and a dysfunctional epithelial barrier contributes to host inflammation and metabolic dysfunction in obesity. Fish oil (FO)-derived n-3 polyunsaturated fatty acids have been shown to improve aspects of the obese phenotype; however, their effect on obese intestinal health is unknown. This study aimed to determine the effect of dietary FO on the intestinal microenvironment, including the microbial community and epithelial barrier, in a mouse model of high-fat diet induced obesity and metabolic dysfunction. Male C57BL/6 mice were fed (12 weeks) either a high-fat diet (HF, 60% fat as kcal) or an isocaloric HF supplemented with Menhaden FO (5.3% kcal, HF + FO). 16S rRNA sequencing was used to determine changes in fecal microbiota. Intestinal (ileum and colon) and epididymal adipose tissue RNA was used to assess biomarkers of barrier integrity and inflammatory status, respectively. Serum was used to assess adipokine concentrations and insulin resistance. HF + FO diet altered the fecal microbiota by decreasing the abundance of Firmicutes and increasing the abundance of members of the Bacteroidetes phyla, as well as increasing the abundance of antiobesogenic Akkermansia muciniphila, compared to HF. Intestinal epithelial barrier functions were improved by HF + FO evidenced by increased mRNA expression of tight junction components, antimicrobial defenses and mucus barrier components. HF + FO-fed mice exhibited improvements in homeostatic model assessment of insulin resistance, oral glucose tolerance and serum adipokine concentrations and epididymal mRNA expression (increased adiponectin and decreased leptin) versus HF. HF + FO improved obese intestinal health and attenuated metabolic dysfunction associated with obesity.

Supplemental estrogen and caloric restriction reduce obesity-induced periprostatic white adipose inflammation in mice.

Obesity is associated with an increased incidence of high-grade prostate cancer (PC) and worse prognosis for PC patients. Recently, we showed in men that obesity-related periprostatic white adipose tissue (WAT) inflammation, characterized by macrophages surrounding dead or dying adipocytes forming crown-like structures, was associated with high-grade PC. Possibly, interventions that suppress periprostatic WAT inflammation will improve outcomes for men with PC. Here, we tested the hypothesis that supplemental 17ß-estradiol (E2) could decrease periprostatic WAT inflammation in obese male mice. Mice were fed a high-fat diet to induce periprostatic WAT inflammation before being treated with supplemental E2. E2 supplementation suppressed caloric intake, induced weight loss, decreased periprostatic WAT inflammation and downregulated the expression of genes linked to inflammation including Cd68, Mcp1 and Tnf. Similar to the effects of E2 supplementation, treatment with diethylstilbestrol, a synthetic estrogen, also suppressed caloric intake and reduced periprostatic WAT inflammation. To determine whether the observed effects of supplemental estrogen could be reproduced by caloric restriction (CR) alone, obese mice were put on a 30% CR diet. Like estrogen treatment, CR was effective in reducing body weight, periprostatic WAT inflammation and the expression of pro-inflammatory genes. Transcriptomic analyses of periprostatic fat showed that obesity was associated with enrichment in inflammatory response pathways, which were normalized by both supplemental E2 and CR. Taken together, these findings strengthen the rationale for future efforts to determine whether either CR or supplemental estrogen will decrease periprostatic WAT inflammation and thereby improve outcomes for men with PC.

Four Weeks of Preoperative Omega-3 Fatty Acids Reduce Liver Volume: a Randomised Controlled Trial.

PURPOSE: Weight loss before bariatric surgery with a low-calorie diet (LCD) has several advantages, including reduction of liver volume and an improved access to the lesser sac. Disadvantages include performing surgery in a state of undernutrition, side effects, costs and patient compliance. Omega-3 fatty acids may serve as an alternative to reduce liver steatosis. MATERIALS AND METHODS: A randomised controlled open-label trial was done to compare the effects of a LCD with Modifast (800 kcal/day) during 2 weeks with 2 g of omega-3 fatty acids a day and a normal diet (2000 kcal/day) during 4 weeks. Total liver volume (TLV) and volume of the left liver lobe (LLL), visceral fat area (VFA) and muscle area (SMA) at the L3-L4 level were measured with MRI before and after preoperative treatment. RESULTS: Sixty-two morbidly obese women undergoing laparoscopic Roux-en-Y gastric bypass surgery (LRYGB) were recruited. In both groups, there was a significant decrease in LLL, TLV and VFA. For LLL and TLV reduction, the LCD had a significantly larger effect (p < 0.05). Only in the LCD group was there a significant decrease in SMA with significantly more side effects and worse compliance. CONCLUSION: Both the LCD and omega-3 diet reduced LLL, TLV and VFA. The LCD outperformed the omega-3 diet in LLL and TLV reduction, but induced significant loss of SMA and had worse compliance due to more side effects. Omega-3 fatty acids may provide a safe and more patient-friendly alternative for a LCD and further research is indicated. TRIAL REGISTRATION: The study is registered at www.clinicaltrials.gov (NCT02206256).

Intrapancreatic fat deposition and visceral fat volume are associated with the presence of diabetes after acute pancreatitis.

Ectopic fat and abdominal adiposity phenotypes have never been studied holistically in individuals after acute pancreatitis (AP). The aim of the study was to investigate phenotypical differences in ectopic fat and abdominal fat between individuals after AP (with and without diabetes) and to determine the role of pancreatitis-related factors. Eighty-four individuals were studied cross-sectionally after a median of 21.5 mo since last episode of AP and were categorized into "diabetes" and "no diabetes" groups. Twenty-eight healthy volunteers were also recruited. With the use of magnetic resonance imaging, intrapancreatic fat percentage, liver fat percentage, visceral fat volume (VFV), subcutaneous fat volume, and visceral-to-subcutaneous (V/S) fat volume ratio were quantified. Analysis of variance was used to investigate the differences in these phenotypes between the groups. All analyses were adjusted for age and sex. Linear regression analysis was used to investigate the association between pancreatitis-related factors and the studied phenotypes. Intrapancreatic fat percentage was significantly higher in the diabetes group (10.2 ± 1.2%) compared with the no diabetes (9.2 ± 1.7%) and healthy volunteers (7.9 ± 1.9%) groups (P < 0.001). VFV was significantly higher in the diabetes (2,715.3 ±1,077.6 cm3) compared with no diabetes (1,983.2 ± 1,092.4 cm3) and healthy volunteer (1,126.2 ± 740.4 cm3) groups (P < 0.001). V/S fat volume ratio was significantly higher in the diabetes (0.97 ± 0.27) compared with no diabetes (0.68 ± 0.42) and healthy volunteer (0.52 ± 0.34) groups (P = 0.001). Biliary AP was associated with significantly higher intrapancreatic fat percentage (ß = 0.67; 95% CI, 0.01, 1.33; P = 0.047). C-reactive protein levels during hospitalization for AP were associated with significantly higher VFV (ß = 3.32; 95% CI, 1.68, 4.96; P < 0.001). In conclusion, individuals with diabetes after AP have higher intrapancreatic fat percentage, VFV, and V/S fat volume ratio. Levels of C-reactive protein during AP are significantly associated with VFV, whereas biliary AP is significantly associated with intrapancreatic fat percentage. NEW & NOTEWORTHY Individuals with diabetes after acute pancreatitis have significantly higher intrapancreatic fat percentage and visceral fat volume compared with individuals without diabetes after acute pancreatitis and healthy controls. C-reactive protein levels during hospitalization for acute pancreatitis and biliary etiology of acute pancreatitis are associated with significantly larger visceral fat and pancreatic fat depots, respectively.

Omega-3 Fatty Acids Attenuate Brain Alterations in High-Fat Diet-Induced Obesity Model.

This study evaluated the effects of omega-3 on inflammation, oxidative stress, and energy metabolism parameters in the brain of mice subjected to high-fat diet-induced obesity model. Body weight and visceral fat weight were evaluated as well. Male Swiss mice were divided into control (purified low-fat diet) and obese (purified high-fat diet). After 6 weeks, the groups were divided into control + saline, control + omega-3, obese + saline, and obese + OMEGA-3. Fish oil (400 mg/kg/day) or saline solution was administrated orally, during 4 weeks. When the experiment completed 10 weeks, the animals were euthanized and the brain and visceral fat were removed. The brain structures (hypothalamus, hippocampus, prefrontal cortex, and striatum) were isolated. Treatment with omega-3 had no effect on body weight, but reduced the visceral fat. Obese animals showed increased inflammation, increased oxidative damage, decreased antioxidant enzymes activity and levels, changes in the Krebs cycle enzyme activities, and inhibition of mitochondrial respiratory chain complexes in the brain structures. Omega-3 treatment partially reversed the changes in the inflammatory and in the oxidative damage parameters and attenuated the alterations in the antioxidant defense and in the energy metabolism (Krebs cycle and mitochondrial respiratory chain). Omega-3 had a beneficial effect on the brain of obese animals, as it partially reversed the changes caused by the consumption of a high-fat diet and consequent obesity. Our results support studies that indicate omega-3 may contribute to obesity treatment.

Anti-obesity effects of Diospyros lotus leaf extract in mice with high-fat diet-induced obesity.

Diospyros (D.) lotus has been demonstrated to have antioxidant and anti­inflammatory properties. The purpose of the present study was to evaluate the effect of D. lotus leaf water extract (DLE) on high­fat diet (HFD)­induced obesity in C57BL/6 mice. The present study first investigated the effect of DLE on the lipid accumulation and triglyceride (TG) contents in 3T3­L1 cells, and the results revealed that treatment with DLE suppressed the lipid accumulation and TG level. Subsequently, the anti­obesity effects of DLE were investigated in vivo. Oral administration of DLE reduced the body weight gain, food efficiency ratio, and liver and visceral fat weight in mice fed with a HFD. DLE administration in these mice also reduced TG, total cholesterol, low­density lipoprotein cholesterol, glucose, insulin and leptin levels, as well as the atherogenic index. Furthermore, DLE administration decreased hepatic steatosis, as well as serum aspartate transaminase, alanine transaminase and alkaline phosphatase levels in mice fed with HFD. It was further observed that treatment of the HFD­fed mice with DLE prevented lipid peroxidation, while it recovered glutathione depletion and the activities of superoxide dismutase, catalase and glutathione peroxidase. In conclusion, the current study suggests that the anti­obesity effect of DLE may provide positive insights as a potential functional food ingredient for the prevention of obesity.

Ascorbic acid inhibits visceral obesity and nonalcoholic fatty liver disease by activating peroxisome proliferator-activated receptor α in high-fat-diet-fed C57BL/6J mice.

BACKGROUND/OBJECTIVES: Ascorbic acid is a known cofactor in the biosynthesis of carnitine, a molecule that has an obligatory role in fatty acid oxidation. Our previous studies have demonstrated that obesity is regulated effectively through peroxisome proliferator-activated receptor α (PPARα)-mediated fatty acid ß-oxidation. Thus, this study aimed to determine whether ascorbic acid can inhibit obesity and nonalcoholic fatty liver disease (NAFLD) in part through the actions of PPARα. DESIGN: After C57BL/6J mice received a low-fat diet (LFD, 10% kcal fat), a high-fat diet (HFD, 45% kcal fat), or the same HFD supplemented with ascorbic acid (1% w/w) (HFD-AA) for 15 weeks, variables and determinants of visceral obesity and NAFLD were examined using metabolic measurements, histology, and gene expression. RESULTS: Compared to HFD-fed obese mice, administration of HFD-AA to obese mice reduced body weight gain, visceral adipose tissue mass, and visceral adipocyte size without affecting food consumption profiles. Concomitantly, circulating ascorbic acid concentrations were significantly higher in HFD-AA mice than in HFD mice. Ascorbic acid supplementation increased the mRNA levels of PPARα and its target enzymes involved in fatty acid ß-oxidation in visceral adipose tissues. Consistent with the effects of ascorbic acid on visceral obesity, ascorbic acid not only inhibited hepatic steatosis but also increased the mRNA levels of PPARα-dependent fatty acid ß-oxidation genes in livers. Similarly, hepatic inflammation, fibrosis, and apoptosis were also decreased during ascorbic acid-induced inhibition of visceral obesity. In addition, serum levels of alanine aminotransferase, aspartate aminotransferase, total cholesterol, and LDL cholesterol were lower in HFD-AA-fed mice than in those of HFD-fed mice. CONCLUSIONS: These results suggest that ascorbic acid seems to suppress HFD-induced visceral obesity and NAFLD in part through the activation of PPARα.

Hypothalamic Gliosis by MRI and Visceral Fat Mass Negatively Correlate with Plasma Testosterone Concentrations in Healthy Men.

OBJECTIVE: This study aimed to determine whether a relationship was evident between gliosis in the mediobasal hypothalamus (MBH) and plasma testosterone concentrations in men. METHODS: A total of 41 adult men (aged 18-50 years) from 23 twin pairs underwent fasting morning blood draw and brain magnetic resonance imaging. T2 relaxation time was used to quantify gliosis in the MBH and control areas in the putamen and amygdala. Plasma concentrations of testosterone and 17ß-estradiol were measured by liquid chromatography-tandem mass spectrometry. Body composition including visceral adiposity was measured by dual x-ray absorptiometry. RESULTS: A negative association was found between MBH T2 relaxation time and plasma concentrations of both free and total testosterone (r = -0.29, P < 0.05 and r = -0.37, P < 0.01, respectively). Visceral adiposity exhibited a negative correlation with plasma total testosterone concentration (r = -0.45, P = 0.001) but a positive correlation with MBH T2 relaxation time (r = 0.24, P = 0.03). The negative correlation between plasma total testosterone and MBH T2 relaxation time remained significant after adjustment for visceral adiposity, age, BMI, and insulin resistance. CONCLUSIONS: In healthy men across a range of BMIs, MBH gliosis was associated with higher visceral adiposity but lower endogenous testosterone. These findings suggest that MBH gliosis could provide novel mechanistic insights into gonadal dysfunction in men with obesity.

Agaricus bisporus supplementation reduces high-fat diet-induced body weight gain and fatty liver development.

Obesity is a global epidemic characterized not only by excessive fat deposition but also by important complications such as nonalcoholic liver steatosis. Beneficial antiobesogenic effects have been described for some mushrooms. The current study aimed to demonstrate the protective effect of Agaricus bisporus (AB) supplementation against the metabolic alterations induced by high-fat-diet (HFD) feeding. Eight-week-old C57BL/6J mice were fed for 10 weeks with one of the following diets: (1) control diet (n = 7), (2) HFD (n = 7), (3) HFD supplemented with 5% AB (n = 9), and (4) HFD supplemented with 10% AB (n = 9). A pair-fed group was also included for the 10% AB group (n = 6). The impact of AB supplementation on food intake, body weight gain, and liver and fat pad weights was examined. Biochemical, histological, and molecular parameters were also analyzed. Dietary supplementation with 10% AB reduced the HFD-induced increase in body, epididymal, and mesenteric fat weights (p < 0.01, p < 0.05, and p < 0.05, respectively). Supplementation with AB also reduced liver damage in a dose-dependent manner (p < 0.01 and p < 0.001). This effect was confirmed by histological analysis that showed that liver steatosis was markedly reduced in mice fed with AB. The beneficial properties of 10% AB supplementation appear to be mediated through a decrease in food intake and via stimulation of mesenteric and hepatic free-fatty acid beta-oxidation, along with a decrease in epidydimal and hepatic expression of CD36. In conclusion, supplementation with AB prevents excessive body weight gain and liver steatosis induced by HFD consumption.

Improvement of insulin resistance via increase of GLUT4 and PPARγ in metabolic syndrome-induced rats treated with omega-3 fatty acid or l-carnitine.

BACKGROUND: Frequent consumption of fructose and saturated fatty acids increase risk of metabolic syndrome (MS). Features of MS include insulin resistance, dyslipidemia, visceral obesity, and hypertension. The aim of this study was to investigate the role of omega-3 and l-carnitine in ameliorating features of MS. METHODS: MS was induced in rats by high-fructose high-fat fed diet for 8 weeks. They were randomly divided into five groups: normal control, MS control group treated with saline, MS groups given omega-3 (260 mg/kg), l-carnitine (200 mg/kg), or metformin (100 mg/kg) daily for 4 weeks. Body weight, relative organ weight, glucose, insulin, adiponectin, and lipid profiles were estimated. Also glucose transporter 4 (GLUT4) content and peroxisome proliferator-activated receptor-gamma (PPARγ) protein expressions were determined. RESULTS: Omega-3 and l-carnitine caused decrease in both MS-induced increase in body weight and glucose similar to metformin. They reduced insulin level and resistance with increased adiponectin, and correction of MS-induced hyperlipidemia. Drugs also increased GLUT4 and PPARγ protein expression compared with MS control group. CONCLUSION: Omega-3 and l-carnitine improve features of MS via increased GLUT4 and PPARγ expression.

Dietary Quercetin Attenuates Adipose Tissue Expansion and Inflammation and Alters Adipocyte Morphology in a Tissue-Specific Manner.

Chronic inflammation in adipose tissue may contribute to depot-specific adipose tissue expansion, leading to obesity and insulin resistance. Dietary supplementation with quercetin or botanical extracts containing quercetin attenuates high fat diet (HFD)-induced obesity and insulin resistance and decreases inflammation. Here, we determined the effects of quercetin and red onion extract (ROE) containing quercetin on subcutaneous (inguinal, IWAT) vs. visceral (epididymal, EWAT) white adipose tissue morphology and inflammation in mice fed low fat, high fat, high fat plus 50 µg/day quercetin or high fat plus ROE containing 50 µg/day quercetin equivalents for 9 weeks. Quercetin and ROE similarly ameliorated HFD-induced increases in adipocyte size and decreases in adipocyte number in IWAT and EWAT. Furthermore, quercetin and ROE induced alterations in adipocyte morphology in IWAT. Quercetin and ROE similarly decreased HFD-induced IWAT inflammation. However, quercetin and red onion differentially affected HFD-induced EWAT inflammation, with quercetin decreasing and REO increasing inflammatory marker gene expression. Quercetin and REO also differentially regulated circulating adipokine levels. These results show that quercetin or botanical extracts containing quercetin induce white adipose tissue remodeling which may occur through inflammatory-related mechanisms.

Tomato Powder Inhibits Hepatic Steatosis and Inflammation Potentially Through Restoring SIRT1 Activity and Adiponectin Function Independent of Carotenoid Cleavage Enzymes in Mice.

SCOPE: Beta-carotene-15,15'-oxygenase (BCO1) and beta-carotene-9',10'-oxygenase (BCO2) metabolize lycopene to biologically active metabolites, which can ameliorate nonalcoholic fatty liver disease (NAFLD). We investigate the effects of tomato powder (TP containing substantial lycopene (2.3 mg/g)) on NAFLD development and gut microbiome in the absence of both BCO1 and BCO2 in mice. METHOD AND RESULTS: BCO1-/- /BCO2-/- double knockout mice were fed a high fat diet (HFD) alone (n = 9) or with TP feeding (n = 9) for 24 weeks. TP feeding significantly reduced pathological severity of steatosis and hepatic triglyceride levels in BCO1-/- /BCO2-/- mice (p < 0.04 vs HFD alone). This was associated with increased SIRT1 activity, nicotinamide phosphoribosyltransferase expression and AMP-activated protein kinase phosphorylation, and subsequently decreased lipogenesis, hepatic fatty acid uptake, and increasing fatty acid ß-oxidation (p < 0.05). TP feeding significantly decreased mRNA expression of proinflammatory genes (tnf-α, il-1ß, and il-6) in both liver and mesenteric adipose tissue, which were associated with increased plasma adiponectin and hepatic adiponectin receptor-2. Multiplexed 16S rRNA gene sequencing was performed using DNA extracted from cecum fecal samples. TP feeding increased microbial richness and decreased relative abundance of the genus Clostridium. CONCLUSION: Dietary TP can inhibit NAFLD independent of carotenoid cleavage enzymes, potentially through increasing SIRT1 activity and adiponectin production and decreasing Clostridium abundance.

Leucine and resistance training improve hyperglycemia, white adipose tissue loss, and inflammatory parameters in an experimental model of type 1 diabetes.

BACKGROUND: Loss of white adipose tissue (WAT), associated with type 1 diabetes (DM1), contributes to increased chronic systemic inflammation. AIM: The aim of this study was to investigate the effects of leucine supplementation and resistance training (RT) in attenuating WAT loss and improving inflammatory parameters and glucose metabolism in DM1 rats. METHODS: Thirty-two male Wistar rats were distributed into four groups: DA (sedentary and supplemented with non-essential amino acids (NEAA)), DL (sedentary and supplemented with leucine), DTA (submitted to RT and supplemented with NEAA) and DTL (submitted to RT and supplemented with leucine). DM1 was induced by streptozotocin (STZ). An 8-week period of RT consisted of climbing a ladder with a progressively increased load, and supplementation was offered in the feed. RESULTS: Glycemia, polyphagia and polydipsia were lower in DL, DTA and DTL groups compared with the DA group by approximately 20% ( p<.0001), 28% ( p=.004) and 64% ( p<.0001), respectively. Weight of total WAT and retroperitoneal adipose tissue (RPAT) were higher by approximately 21% ( p=.01) and 54% ( p=.0004), respectively, in DL, DTA and DTL groups compared with DA. However, gene expression of adiponectin and leptin in RPAT was only increased by RT (DTA and DTL) compared with DA and DL by approximately 93% ( p<.0001) and 78% ( p=.0002), respectively. Similarly, the levels of adiponectin in the serum, tissue IL-10 (RPAT) and serum IL-10 were only increased in DTA and DTL compared with DA and DL by approximately 31% ( p=.03), 45% ( p=.0009) and 35% ( p=.003), respectively. CONCLUSIONS: Both interventions, isolated or together, reduced hyperglycemia and excessive loss of WAT, but RT was the main factor responsible for attenuating inflammation.

Short-term vitamin E treatment impairs reactive oxygen species signaling required for adipose tissue expansion, resulting in fatty liver and insulin resistance in obese mice.

OBJECTIVES: The use of antioxidant therapy in the treatment of oxidative stress-related diseases such as cardiovascular disease, diabetes or obesity remains controversial. Our aim is to demonstrate that antioxidant supplementation may promote negative effects if used before the establishment of oxidative stress due to a reduced ROS generation under physiological levels, in a mice model of obesity. METHODS: C57BL/6J mice were fed with a high-fat diet for 14 weeks, with (OE group) or without (O group) vitamin E supplementation. RESULTS: O mice developed a mild degree of obesity, which was not enough to induce metabolic alterations or oxidative stress. These animals exhibited a healthy expansion of retroperitoneal white adipose tissue (rpWAT) and the liver showed no signs of lipotoxicity. Interestingly, despite achieving a similar body weight, OE mice were insulin resistant. In the rpWAT they presented a reduced generation of ROS, even below physiological levels (C: 1651.0 ± 212.0; O: 3113 ± 284.7; OE: 917.6 ±104.4 RFU/mg protein. C vs OE p< 0.01). ROS decay may impair their action as second messengers, which could account for the reduced adipocyte differentiation, lipid transport and adipogenesis compared to the O group. Together, these processes limited the expansion of this fat pad and as a consequence, lipid flux shifted towards the liver, causing steatosis and hepatomegaly, which may contribute to the marked insulin resistance. CONCLUSIONS: This study provides in vivo evidence for the role of ROS as second messengers in adipogenesis, lipid metabolism and insulin signaling. Reducing ROS generation below physiological levels when the oxidative process has not yet been established may be the cause of the controversial results obtained by antioxidant therapy.

Chronic High Dose Zinc Supplementation Induces Visceral Adipose Tissue Hypertrophy without Altering Body Weight in Mice.

The trace element zinc plays an important role in human life. Zinc deficiency impairs growth, reproduction, metabolism and immunity in both human and animals. Thus, zinc supplementation is recommended in daily life. However, the effect of long-term chronic zinc supplementation on adipose homeostasis has not been well elucidated. In the current study, mice were supplemented with zinc sulfate in the drinking water for 20 weeks. The results suggested that chronic zinc supplementation impaired systemic glucose clearance after exogenous insulin or glucose challenges, as compared to the control mice. Further study revealed that chronic zinc supplementation made no difference to body weight, but increased visceral adipose tissue weight and adipocyte size. In addition, gene expression of leptin and IL6 in the visceral adipose tissue of zinc-supplemented mice were higher than those of control mice. Moreover, serum level of leptin of the zinc-supplemented mice was twice as high as that of the control mice. Besides, phosphorylation level of AKT T308 was attenuated in the perirenal adipose tissue of zinc-supplemented mice. In comparison, the expression of macrophage marker genes and lipogenic genes were not affected by chronic zinc supplementation, but the protein levels of FAS and SCD1 decreased or tended to decrease in the perirenal adipose tissue of zinc-supplemented mice, as compared to the control mice. Our findings suggest that chronic high dose zinc supplementation induces visceral adipose tissue hypertrophy and impairs AKT signaling in perirenal adipose tissue.

Piperonal attenuates visceral adiposity in mice fed a high-fat diet: potential involvement of the adenylate cyclase-protein kinase A dependent pathway.

SCOPE: Piperonal is an aromatic compound found in vanilla and has a floral odor resembling vanillin. This study was aimed to test whether piperonal attenuates visceral adiposity induced by a high-fat diet (HFD) in mice and to explore the underlying molecular mechanisms. METHODS AND RESULTS: Male C57BL/6N mice were fed a normal diet, HFD, or 0.05% piperonal-supplemented HFD (PSD) for 10 weeks. PSD-fed mice showed attenuation of body weight gain, total visceral fat pad weights, and plasma lipid levels compared to HFD-fed mice. Piperonal supplementation of the HFD increased the mRNA expression of certain isotypes of adenylate cyclase (Adcy) and protein kinase A (PKA) in the white adipose tissue (WAT) of mice. The adipogenesis-related genes were downregulated, whereas fatty acid oxidation- and thermogenesis-related genes were upregulated in the WAT of PSD-fed mice compared to those in HFD-fed mice. Piperonal directly activated Adcy by decreasing the Km for its substrate (ATP) in plasma membranes prepared from the WAT of mice. Furthermore, piperonal-induced inhibition of adipocyte differentiation and elevation of Adcy and PKA activities in 3T3-L1 cells were abrogated by an Adcy inhibitor. CONCLUSION: The anti-adipogenic effect of piperonal in mice fed the high-fat diet appears to be associated with increased Adcy-PKA signaling in WAT.