White Adipose Tissue Weight Research Articles

506-P: Regulation of ANGPTL3 by SEL1L-HRD1 ER-Associated Degradation

Angiopoietin-like 3 (ANGPTL3) is a liver-derived circulating factor critical for systemic lipid metabolism via the inhibition of lipoprotein lipase (LPL). Loss-of-function mutations in ANGPTL3 in humans and mice reduce circulating levels of triglycerides. Here, we report the discovery of a novel mechanism regulating the biosynthesis and maturation of nascent ANGPTL3 in the endoplasmic reticulum (ER). Mice with acute or chronic liver-specific deletion of SEL1L-HRD1, the most conserved branch of mammalian endoplasmic reticulum (ER)-associated degradation (ERAD) machinery, exhibit significantly lower levels of triglyceride and cholesterol in the serum with reduced weights of both epididymal and inguinal white adipose tissues (WAT). Various proteomics screenings have identified ANGPTL3 as a possible link between SEL1L-HRD1 ERAD and hypolipidemia. Indeed, ANGPTL3 is a bona fide endogenous substrate of SEL1L-HRD1 ERAD in the liver and in the absence of ERAD, ANGPTL3 protein is retained in the ER, forming high-molecular weight aggregates. This abnormal ER retention of ANGPTL3 accounts for a reduced circulating level of ANGPTL3, therefore contributing to hypolipidemia in ERAD-deficient mice. Together, this study not only uncovers a novel regulator for ANGPTL3 and novel targets in the treatment of hyperlipidemia in obesity and diabetes. Disclosure L.Zhou: None. L.Lin: None. S.Sun: None. L.Qi: None.

Lactobacillus paracasei L9 ameliorated obesity-associated metabolic parameters and relevant gut microbiota in mice fed a high-fat diet

The purpose of the present study was to determine whether Lactobacillus paracasei L9 (L9) supplementation prevents diet-induced obesity in C57BL/6J mice. Four-week-old mice were fed a high-fat diet (HFD) for 12 weeks and then supplemented with or without L9 for another 12 weeks. Weight gain, white adipose tissue weight, plasma lipid levels of total cholesterol, triglyceride, and low-density lipoprotein-cholesterol were significantly increased in the HFD group compared with those in the control group and were decreased by L9 treatment. The fat deposits in the liver and epididymal adipose tissue were increased in the HFD group compared with the normal chow diet group and decreased by L9 treatment. Reverse transcriptase-polymerase chain reaction analyses revealed that L9 suppressed pro-inflammatory cytokine and lipid synthesis–related genes in epididymal adipose tissue. This study used Illumina Miseq sequencing to explore alterations of the gut microbiome. L9 ameliorated HFD-induced structural dysbiosis and gut bacteria that were positively related with obesity phenotypes were obviously decreased. Altogether, the findings indicate that administration of L9 ameliorates HFD-induced hyperlipidemia and lipid accumulation in liver and inflammation associated with intestinal dysbiosis in obese mice. These findings suggest that L9 supplementation may provide a natural alternative to attenuate obesity.

The combination of metformin with morin alleviates hepatic steatosis via modulating hepatic lipid metabolism, hepatic inflammation, brown adipose tissue thermogenesis, and white adipose tissue browning in high-fat diet-fed mice

AimThe valuable effects of metformin (MET) and morin (MOR) in the improvement of NAFLD have been proposed, nevertheless, their combination impacts were not investigated so far. We determined the therapeutic effects of combined MET and MOR treatment in high-fat diet (HFD)-induced Non-alcoholic fatty liver disease (NAFLD) mice. MethodsC57BL/6 mice were fed on an HFD for 15 weeks. Animals were allotted into various groups and supplemented with MET (230 mg/kg), MOR (100 mg/kg), and MET + MOR (230 mg/kg + 100 mg/kg). Key findingsMET in combination with MOR reduced body and liver weight in HFD-fed mice. A significant decrease in fasting blood glucose and improvement in glucose tolerance was observed in HFD mice treated with MET + MOR. Supplementation with MET + MOR led to a decline in hepatic triglyceride levels and this impact was associated with diminished expression of fatty-acid synthase (FAS) and elevated expression of carnitine palmitoyl transferase 1 (CPT1) and phospho-Acetyl-CoA Carboxylase (p-ACC). Moreover, MET combined with MOR alleviates hepatic inflammation through the polarization of macrophages to the M2 phenotype, decreasing the infiltration of macrophages and lowering the protein level of NF-kB. MET and MOR in combination reduce the size and weight of epididymal white adipose tissue (eWAT), and subcutaneous WAT (sWAT), whereas improves cold tolerance, BAT activity, and mitochondrial biogenesis. Combination therapy results in stimulating brown-like adipocyte (beige) formation in the sWAT of HFD mice. SignificanceThese results suggest that the combination of MET and MOR has a protective effect on hepatic steatosis, which may use as a candidate therapeutic for the improvement of NAFLD.

Standardized Sanguisorba officinalis L. Extract Inhibits Adipogenesis and Promotes Thermogenesis via Reducing Oxidative Stress.

Obesity produces many health problems, including systemic oxidative stress. This study comprehensively investigated the effects of Sanguisorba officinalis L. extract (SO) as an antioxidant on abnormal lipid accumulation and oxidative stress in 3T3-L1 adipocytes and high-fat diet (HFD)-induced obese mice (n = 48). We evaluated the anti-adipogenic and antioxidant effects of SO on 3T3-L1 by cell viability, Oil red O staining, and NBT assays. The ameliorative effects of SO in HFD-induced C57BL/6J mice were investigated by measuring body weight, serum lipids, adipocyte size, hepatic steatosis, AMPK pathway-related proteins, and thermogenic factors. In addition, the effect of SO on oxidative stress in obese mice was evaluated by the activity of antioxidant enzymes and the production of lipid peroxidation products and ROS production in adipose tissue. We found that SO dose-dependently decreased lipid accumulation and ROS production in 3T3-L1 adipocytes. In C57BL/6J obese mice, SO (above 200 mg/kg) attenuated the HFD-induced gain in body weight and white adipose tissue (WAT) weight without affecting appetite. SO also decreased serum glucose, lipid, and leptin levels and attenuated adipocyte hypertrophy and hepatic steatosis. Furthermore, SO increased the expression of SOD1 and SOD2 in WAT, decreased ROS and lipid peroxides, and activated the AMPK pathway and thermogenic factors. In summary, SO reduces oxidative stress in adipose tissue by increasing antioxidant enzyme activity and improves obesity symptoms through AMPK-pathway-regulated energy metabolism and mitochondrial respiratory thermogenesis.

The Preventive Effect of Exercise and Oral Branched-Chain Amino Acid Supplementation on Obesity-Induced Brain Changes in Ldlr-/-.Leiden Mice.

Exercise and dietary interventions are promising approaches to tackle obesity and its obesogenic effects on the brain. We investigated the impact of exercise and possible synergistic effects of exercise and branched-chain amino acids (BCAA) supplementation on the brain and behavior in high-fat-diet (HFD)-induced obese Ldlr-/-.Leiden mice. Baseline measurements were performed in chow-fed Ldlr-/-.Leiden mice to assess metabolic risk factors, cognition, and brain structure using magnetic resonance imaging. Thereafter, a subgroup was sacrificed, serving as a healthy reference. The remaining mice were fed an HFD and divided into three groups: (i) no exercise, (ii) exercise, or (iii) exercise and dietary BCAA. Mice were followed for 6 months and aforementioned tests were repeated. We found that exercise alone changed cerebral blood flow, attenuated white matter loss, and reduced neuroinflammation compared to non-exercising HFD-fed mice. Contrarily, no favorable effects of exercise on the brain were found in combination with BCAA, and neuroinflammation was increased. However, cognition was slightly improved in exercising mice on BCAA. Moreover, BCAA and exercise increased the percentage of epididymal white adipose tissue and muscle weight, decreased body weight and fasting insulin levels, improved the circadian rhythm, and transiently improved grip strength. In conclusion, BCAA should be supplemented with caution, although beneficial effects on metabolism, behavior, and cognition were observed.

Lycopene prevents non-alcoholic fatty liver disease through regulating hepatic NF-κB/NLRP3 inflammasome pathway and intestinal microbiota in mice fed with high-fat and high-fructose diet.

Lycopene (LY) belongs to carotenoids and is abundant in red fruits and vegetables. Several previous studies suggested that LY is beneficial for ameliorating non-alcoholic fatty liver disease (NAFLD), while the potential mechanisms are unclear. The present study aimed to clarify the potential mechanisms of LY in preventing NAFLD via exploring the hepatic NF-κB/NLRP3 inflammasome pathway and intestinal microbiota composition in high-fat and high-fructose diet (HFFD)-fed mice. Fifty eight-week-old male C57BL/6J mice were randomly assigned into 5 groups: Normal control group (NC); HFFD group; HFFD with low dose of lycopene group (LLY, 20 mg/kg/d); HFFD with high dose of lycopene group (HLY, 60 mg/kg/d) and HFFD with resveratrol group (RSV, 50 mg/kg/d, positive control). After 8 weeks, feces were collected and the 12 h fasted mice were sacrificed to acquire tissues and blood for parameters measurement. The results showed that the mice in LLY, HLY and RSV groups had significantly lower body weight gain, weight of white adipose tissue, serum levels of high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), lipopolysaccharide (LPS), alanine aminotransferase (ALT), and hepatic concentrations of triglyceride (TG) and interleukin-6 (IL-6) than that in the HFFD group (p < 0.05). HLY and RSV groups also displayed lower serum levels of TG, total cholesterol (TC) and hepatic levels of tumor necrosis factor-α (TNF-α) than the HFFD group (p < 0.05). Liver protein expressions of NLRP3, Pro-Caspase-1, Caspase-1 and NF-κB were lower in the LLY, HLY and RSV groups than those in the HFFD group (p < 0.05). The feces of LY -treated mice had higher relative levels of SCFAs producing bacteria Allobaculum and lower destructive bacteria, including Firmicutes, Lachnospiraceae_NK4A136_group, Desulfovibrio, and Alistipes over the HFFD group (p < 0.05). RSV group also displayed lower fecal levels of Lachnospiraceae_NK4A136_group, Desulfovibrio, and Alistipes than the HFFD group (p < 0.05). In conclusion, LY might prevent NAFLD by suppressing hepatic NF-κB/NLRP3 inflammasome pathway and attenuating gut microbiota dysbiosis.

Multi-omics reveals hypertrophy of adipose tissue and lipid metabolism disorder via mitochondria in young mice under real-ambient exposure to air pollution.

Air pollution has become one of the most serious health risks as a result of industrialization, especially in developing countries. More attention has been drawn to the relationship between obesity/overweight and fine particulate matter (PM2.5). Especially for susceptible populations, the impact of air pollution on children and adolescents has attracted more public attentions. However, the detailed underlying mechanism influencing obesity or overweight under PM2.5 exposure is still unknown. Therefore, young mice were exposed to PM2.5 using the real-ambient exposure system that we previously established in Shijiazhuang city. Compared with the traditionally concentrated air particle (CAP) system, our real-ambient exposure system provides similar PM2.5 concentrations and characteristics as outdoor ambient air and minimizes the influence of external interfering factors. After 8weeks of exposure to PM2.5, the weight of gonadal white adipose tissue (gWAT) and subcutaneous white adipose tissue (sWAT) was considerably increased, accompanied by a significantly enlarged size of adipocytes in sWAT. Importantly, multiomics analysis indicated altered metabolites involved in the lipid metabolism pathway, and transcriptomic analysis revealed notably changed signaling pathways related to fatty acid metabolism. Moreover, the mtDNA copy number, mitochondrial activity and fatty acid oxidation (FAO) were increased in the liver under PM2.5 exposure. Taken together, our research investigated the hypotrophy of adipose tissue in young mice, supported an imbalance in lipid metabolism based on multiomics analysis, and revealed disordered mitochondrial function under PM2.5 exposure. Our study provided new insight into the hazardous effects of air pollution, and extended our understanding on the underlying mechanism.

Calebin-A prevents HFD-induced obesity in mice by promoting thermogenesis and modulating gut microbiota.

Obesity is one of the complications of sedentary lifestyle and high-calorie food intake which become a global problem. Thermogenesis is a novel way to promote anti-obesity by consuming energy as heat rather than storing it as triacylglycerols. Over the last decade, growing evidence has identified the gut microbiota as a potential factor in the pathophysiology of obesity. Calebin A is a non-curcuminoid novel compound derived from the rhizome of medicinal turmeric with putative anti-obesity effects. However, its ability on promoting thermogenesis and modulating gut microbiota remain unclear. C57BL/6J mice were fed either normal diet or high-fat diet (HFD) supplement with calebin A (0.1 and 0.5%) diet for 12 weeks. The composition of the gut microbiota was assessed by analyzing 16S rRNA gene sequences. Mice treated with calebin A shows a remarkable alteration in microbiota composition compared with that of normal diet-fed or HFD-fed mice and is characterized by an enrichment of Akkermansia, Butyricicoccus, Ruminiclostridium_9, and unidentified_Ruminococcaceae. We also explored that calebin A reduce the weight and blood sugar of mice that are induced by HFD, and show a dose-dependent reaction. Moreover, calebin A decreases the weight of white, beige, and brown adipose tissue, and also restores liver weight. In cold exposure experiments, calebin A can better maintain rectal temperature through thermogenesis. In summary, calebin A has a good thermogenesis function and is effective in anti-obesity. It can be used as a novel gut microbiota modulator to prevent HFD-induced obesity.

3-OH Phloretin Inhibits High-Fat Diet-Induced Obesity and Obesity-Induced Inflammation by Reducing Macrophage Infiltration into White Adipose Tissue.

Phloretin and its glycoside phlorizin have been reported to prevent obesity induced by high-fat diet (HFD), but the effect of 3-OH phloretin, a catechol metabolite of phloretin, has not been investigated. In this study, we investigated the anti-obesity effects of phloretin and 3-OH phloretin in HFD-fed mice. The body weight gain induced by HFD was more inhibited by administration of 3-OH phloretin than by phloretin. The increases in fat mass, white adipose tissue (WAT) weight, adipocyte size, and lipid accumulation by HFD were also remarkably inhibited by 3-OH phloretin and, to a lesser extent, by phloretin. The HFD-induced upregulation of chemokines and pro-inflammatory cytokines was suppressed by 3-OH phloretin, preventing M1 macrophages from infiltrating into WAT and thereby reducing WAT inflammation. 3-OH phloretin also showed a more potent effect than phloretin on suppressing the expression of adipogenesis regulator genes, such as PPARγ2, C/EBPα, FAS, and CD36. Fasting blood glucose and insulin levels increased by HFD were diminished by the administration of 3-OH phloretin, suggesting that 3-OH phloretin may alleviate obesity-induced insulin resistance. These findings suggested that 3-OH phloretin has the potential to be a natural bioactive compound that can be used in the prevention or treatment of obesity and insulin resistance.

A transdermal treatment with MC903 ameliorates diet-induced obesity by reducing visceral fat and increasing myofiber thickness and energy consumption in mice

AimMC903 is a synthetic derivative of vitamin D3 that has been designed to diminish its impact on calcium metabolism and is clinically used as a transdermal reagent for psoriasis. Animal studies showed that an oral or intraperitoneal vitamin D3 treatment prevented the development of obesity. In contrast, the bioavailability of orally administered vitamin D3 is reported to be low in obese patients. In the current study, we aimed to investigate the impact of a transdermal treatment with MC903 in established obese mice. We further studied the underlying mechanisms of MC903-mediated metabolic improvement.Materials and methodsMale C57BL/6 J mice were fed standard chow or a 60% high-fat diet (HFD) for 7 weeks, and a transdermal treatment with MC903 on the ear auricle was initiated thereafter. The metabolic profiles of mice were analyzed during 4 weeks of treatment, and mice were dissected for histological and gene expression analyses. The direct impacts of MC903 and vitamin D3 were investigated using 3T3-L1 adipocytes and C2C12 myotubes in vitro.ResultsHFD-fed mice showed significant increases in body and epididymal white adipose tissue (eWAT) weights with enlarged adipocytes. They exhibited glucose intolerance, decreased oxygen consumption, and chronic inflammation in eWAT. The transdermal treatment with MC903 significantly ameliorated these metabolic abnormalities in HFD-fed mice without affecting food consumption. In accordance with enhanced energy metabolism, myofiber diameters and the expression of uncoupling protein 3 (UCP3) in the gastrocnemius and soleus muscle were significantly increased in MC903-treated HFD mice. In addition, vitamin D3 and MC903 both suppressed adipogenic differentiation and enhanced lipolysis in 3T3-L1 adipocytes, and increased UCP3 expression in cultured C2C12 myotubes. Furthermore, MC903 increased oxygen consumption and UCP3 knockdown significantly decreased them in C2C12 myotubes.ConclusionsA transdermal treatment with MC903 increased myofiber diameter and energy metabolism and decreased visceral fat accumulation, thereby improving obesity and glucose intolerance in mice.

Tschimganidine reduces lipid accumulation through AMPK activation and alleviates high-fat diet-induced metabolic diseases

Obesity increases the risk of mortality and morbidity because it results in hypertension, heart disease, and type 2 diabetes. Therefore, there is an urgent need for pharmacotherapeutic drugs to treat obesity. We performed a screening assay using natural products with anti-adipogenic properties in 3T3-L1 cells and determined that tschimganidine, a terpenoid from the Umbelliferae family, inhibited adipogenesis. To evaluate the anti-obesity effects of tschimganidine in vivo. Mice were fed either a normal chow diet (NFD) or a high-fat chow diet (HFD) with or without tschimganidine for 12 weeks. Treatment with tschimganidine decreased lipid accumulation and adipogenesis, accompanied by reduced expression of adipogenesis and lipid accumulation-related factors. Tschimganidine significantly increased the phosphorylation of AMP-activated protein kinase (AMPK) and decreased that of AKT. Depletion of AMPK relieved the reduction in lipid accumulation resulting from tschimganidine treatment. Moreover, tschimganidine administration drastically reduced the weight and size of both gonadal white adipose tissue (WAT) and blood glucose levels in high-fat diet-induced obese mice. We suggest that tschimganidine is a potent anti-obesity agent, which impedes adipogenesis and improves glucose homeostasis. Tschimganidine can then be evaluated for clinical application as a therapeutic agent.

A Complex of Type I Platelet-Activating Factor Acetylhydrolase (PAF-AH) Catalytic Subunits Switches from α1/α2 Heterodimer to α2/α2 Homodimer during Adipocyte Differentiation of 3T3-L1 Cells.

Platelet-activating factor acetylhydrolase (PAF-AH) hydrolyzes an acetyl ester at the sn-2 position of platelet-activating factor (PAF), thereby mediating a variety of biological functions. PAF-AH is found in three isoforms: Type I PAF-AH (PAF-AH I) and Type II PAF-AH (PAF-AH II) are intracellular enzymes whereas plasma PAF-AH is characterized by association with lipoprotein in plasma. PAF-AH I forms a tetramer constituted by two catalytic subunits (α1 and α2) with β regulatory subunits. We recently showed that a deficiency of PAF-AH I catalytic subunits in male mice caused an increase of body weight, food intake, and white adipose tissue (WAT) weight. In this study, we examined whether the expression of this enzyme was altered in the differentiation of 3T3-L1 preadipocytes into adipocytes. The amount of PAF-AH I α1 subunit protein was significantly reduced in 3T3-L1 differentiation, while the amount of the PAF-AH I α2 subunit was not changed. Immunoprecipitation analysis of 3T3-L1 differentiation showed that the complex of PAF-AH I catalytic subunits was changed from α1/α2 heterodimer to α2/α2 homodimer. Our findings suggest that changes in PAF-AH I catalytic subunits are involved in adipocyte differentiation of 3T3-L1 and obesity in mice.

Dose-Related Regulatory Effect of Raspberry Polyphenolic Extract on Cecal Microbiota Activity, Lipid Metabolism and Inflammation in Rats Fed a Diet Rich in Saturated Fats.

The amount of berry polyphenols required to exert health-promoting effects seems to be difficult to achieve by fresh fruit ingestion, so polyphenol-rich extracts could be considered a dietary alternative. In the present study, laboratory rats were fed high-fat diets supplemented with 0.1 or 0.3% raspberry polyphenols from pomace, with the former dose reflecting the amount of polyphenols consumed with a glass of fresh raspberries. It was hypothesized that beneficial changes in blood and hepatic tissue related to lipid metabolism would accompany both treatments, but the health-promoting effect would be more noticeable with the higher dose of extract. This hypothesis was confirmed, and the high dose of raspberry polyphenols was better than the low dose extract in terms of decreased epididymal white adipose tissue weight, hepatic triglyceride content, PPARγ and SREBP-1c expression in the liver, and plasma IL-6 concentration, as well as increased acetic acid concentration in the cecal digesta. These effects might be partially associated with the enhanced content of ellagitannin and anthocyanin metabolites found in the blood plasma of rats administered the high dose of the extract. The results showed that this extract could be considered a dietary vehicle to provide an amount of raspberry polyphenols that could promote health.

Mentha canadensis attenuates adiposity and hepatic steatosis in high-fat diet-induced obese mice.

Obesity is a major risk factor for metabolic syndrome, a global public health problem. Mentha canadensis (MA), a traditional phytomedicine and dietary herb used for centuries, was the focus of this study to investigate its effects on obesity. Thirty-five male C57BL/6J mice were randomly divided into 2 groups and fed either a normal diet (ND, n = 10) or a high-fat diet (HFD, n = 25) for 4 weeks to induce obesity. After the obesity induction period, the HFD-fed mice were randomly separated into 2 groups: one group continued to be fed HFD (n = 15, HFD group), while the other group was fed HFD with 1.5% (w/w) MA ethanol extract (n = 10, MA group) for 13 weeks. The results showed that body and white adipose tissue (WAT) weights were significantly decreased in the MA-supplemented group compared to the HFD group. Additionally, MA supplementation enhanced energy expenditure, leading to improvements in plasma lipids, cytokines, hepatic steatosis, and fecal lipids. Furthermore, MA supplementation regulated lipid-metabolism-related enzyme activity and gene expression, thereby suppressing lipid accumulation in the WAT and liver. These findings indicate that MA has the potential to improve diet-induced obesity and its associated complications, including adiposity, dyslipidemia, hepatic steatosis, and inflammation.

Lactobacillus rhamnosus GG administration partially prevents diet-induced insulin resistance in rats: a comparison with its heat-inactivated parabiotic.

Insulin resistance and type 2 diabetes are obesity-related health alterations, featuring an ever-increasing prevalence. Besides inadequate feeding patterns, gut microbiota alterations stand out as potential contributors to these metabolic disturbances. The aim of this study was to investigate whether the administration of a probiotic (Lactobacillus rhamnosus GG) effectively prevents diet-induced insulin resistance in rats and to compare these potential effects with those exerted by its heat-inactivated parabiotic. For this purpose, 34 male Wistar rats were fed a standard or a high-fat high-fructose diet, alone or supplemented with viable or heat-inactivated Lactobacillus rhamnosus GG. The body and white adipose tissue weight increases, induced by the obesogenic diet, were prevented by probiotic and parabiotic administration. The trend towards higher basal glucose levels and significantly higher serum insulin concentration observed in the non-treated animals fed with the obesogenic diet were effectively reverted by both treatments. Similar results were also found for serum adiponectin and leptin, whose levels were brought back by the probiotic and parabiotic administration to values similar to those of the control animals. Noteworthily, parabiotic administration significantly reduced skeletal muscle triglyceride content and activated CPT-1b compared to the non-treated animals. Finally, both treatments enhanced Akt and AS160 phosphorylation in the skeletal muscle compared to the non-treated animals; however, only parabiotic administration increased GLUT-4 protein expression in this tissue. These results suggest that heat-inactivated Lactobacillus rhamnosus GG seem to be more effective than its probiotic of origin in preventing high-fat high-fructose diet-induced insulin resistance in rats.

Dietary Combination of Fish Oil and Soy β-Conglycinin Inhibits Fat Accumulation and Reduces Blood Glucose Levels by Altering Gut Microbiome Composition in Diabetic/Obese KK-A y Mice.

Dietary fish oil containing n-3 polyunsaturated fatty acids provides health benefits by lowering lipid levels in the liver and serum. β-Conglycinin (βCG) is a major constituent protein in soybean with many physiological effects, such as lowering blood triglyceride levels, preventing obesity and diabetes, and improving hepatic lipid metabolism. However, the combined effects of fish oil and βCG remain unclear. Here, we investigated the effects of a dietary combination of fish oil and βCG on lipid and glucose parameters in diabetic/obese KK-A y mice. KK-A y mice were divided into three groups: control, fish oil, and fish oil + βCG; these groups were fed a casein-based diet containing 7% (w/w) soybean oil, a casein-based diet containing 2% (w/w) soybean oil and 5% (w/w) fish oil, and a βCG-based diet containing 2% (w/w) soybean oil and 5% (w/w) fish oil, respectively. The effects of the dietary combination of fish oil and βCG on blood biochemical parameters, adipose tissue weight, expression levels of fat- and glucose metabolism-related genes, and cecal microbiome composition were evaluated. The total white adipose tissue weight (p < 0.05), levels of total serum cholesterol (p < 0.01), triglyceride (p < 0.01), and blood glucose (p < 0.05), and expression levels of fatty acid synthesis-related genes (including Fasn (p < 0.05) and Acc (p < 0.05)), and glucose metabolism-related genes (such as Pepck (p < 0.05)) were lower in the fish oil and fish oil + βCG groups than in the control group. Furthermore, the relative abundance of Bacteroidaceae and Coriobacteriaceae differed significantly between the fish oil + βCG and control groups. These findings suggest that dietary intake of fish oil + βCG may prevent obesity and diabetes, alleviate lipid abnormalities, and alter the gut microbiome composition in diabetic/obese KK-A y mice. Further research is needed to build on this study to evaluate the health benefits of major components of Japanese food.

PS-B11-6: ENDOTHELIAL GHRELIN RECEPTOR INCREASE WHITE FAT WEIGHT THROUGH ACTIVATION OF MTOR-PPARGAMMA PATHWAY

Ghrelin secretion from the stomach acts on peripheral tissues to cause weight gain and fat accumulation in white adipose tissue (WAT). The role of endothelial growth hormone secretagogue-receptor (GHSR) in lipid accumulation was evaluated by restoring the expression of GHSR only in the endothelial cells of GHSR-deficient mice using the Cre-LoxP system (GHSR-EC). Radioisotope (RI) -labeled H-triolein was orally administered to evaluate lipid uptake in WAT. GHSR-deficient mice had reduced RI uptake in WAT compared to control mice, and GHSR-EC mice recovered the reduced RI uptake in GHSR-deficient mice. Furthermore, the body weight and WAT weight of GHSR-deficient mice after high-fat diet loading were significantly decreased compared with control mice, but increased in GHSR-EC mice. In vitro studies, ghrelin stimulation increased the uptake of free fatty acids by GHSR-mediated activation of the mTOR pathway and increased expression of PPARgamma. From these results, ghrelin takes up lipids via endothelial GHSR and contributes to fat accumulation in white adipose tissue.

Modulation of PPARα-thermogenesis gut microbiota interactions in obese mice administrated with zingerone.

This study aimed to uncover the potential effects of zingerone (ZIN), one of the bioactive compounds in ginger, on the development of obesity as well as the mechanisms responsible for these effects in C57BL/6J mice fed with a high-fat diet (HFD). Supplementation with 0.2% (wt/wt) zingerone for 16 weeks significantly reduced the final body weight, liver weight, and epididymal white adipose tissue (eWAT) weight without changing the food intake of the mice when compared with the HFD group. The hyperlipidemia of HFD-fed mice was ameliorated after zingerone administration, including decreased plasma triacylglycerol (TG) and total cholesterol (TC) level. The lipid content in liver was lower and the adipocyte size in eWAT and inguinal white adipose tissue (iWAT) was smaller in HFD + ZIN-fed mice compared with HFD group. Zingerone also binds with nuclear hormone receptor peroxisome proliferator-activated receptor alpha (PPARα) with an optimal docking energy of -7.31 kJ/mol. Uncoupling protein 1 (UCP1), PPAR-γ coactivator-1α (PGC-1α), and PR domain containing 16 (PRDM16), the downstream genes of PPAR which are related to thermogenic function of adipocytes, were significantly increased in both brown adipose tissue (BAT) and inguinal white adipose tissue (iWAT) after zingerone administration, in comparison with HFD fed mice. Zingerone intake also restructured the community composition of gut microbiota. The ratio of Firmicutes to Bacteroidetes was decreased, and the relative abundance of Akkermansia_mucinphila was increased. Zingerone can attenuate obesity and related symptoms in HFD-fed mice, probably through the modulation of PPARα-thermogenesis-gut microbiota interactions. © 2022 Society of Chemical Industry.

Timing of Medium-Chain Triglyceride Consumption Modulates Effects in Mice with Obesity Induced by a High-Fat High-Sucrose Diet

The prevalence of obesity is increasing worldwide, and obesity can cause type 2 diabetes, atherosclerosis, hypertension, cardiovascular disease, and cancer. Intake of medium-chain triglycerides (MCTs) containing medium-chain fatty acids reduces body fat and insulin resistance in rodents and humans. This study aimed to determine how the timing of MCT consumption affects obesity and metabolic dysfunction induced in mice by a high-fat high-sucrose diet (HFHSD). Mice received an HFHSD with or without MCT (M-HFHSD) during either the active or rest phase for 9 weeks. Significant reduction in body weight, white adipose tissue (WAT) weight, and adipocyte size in epididymal WAT (eWAT) and improved insulin sensitivity in mice fed with M-HFHSD during the active but not the rest phase were observed. The consumption of M-HFHSD during both active and rest phases increased glucose tolerance. Phosphorylated Akt was more abundant in the gastrocnemius muscles and eWAT of M-HFHSD-fed mice than in those fed HFHSD during the active phase. The mRNA and protein expression of lipogenic genes increased in the eWAT of mice fed M-HFHSD compared with those fed HFHSD. Feeding with M-HFHSD during the active phase significantly increased the abundance of phosphorylated Ser563 and 660 of hormone-sensitive lipase and its upstream protein kinase A in eWAT. These results indicated that the timing of consumption modulates the effects of MCT on eWAT hypertrophy and glucose and lipid metabolism in mice.

The synergistic effect of sea cucumber saponins and caffeine on preventing obesity in high-fat diet-fed mice by extending the action duration of caffeine.

Sea cucumber saponins (SCSs) exhibit a unique structure and high bioactivities and might have specialized implications on caffeine metabolic process by altering the activity of N-demethylation enzyme CYP1A2. The present study aimed to clarify the effects of SCS on caffeine metabolism in vivo and in vitro, as well as the synergistic anti-obesity effect of SCS and caffeine on high-fat diet-induced obese mice. Results found that SCS administration significantly postponed the elimination rate of caffeine and its metabolites in vivo, and further study found CYP1A2-mediated caffeine metabolism was remarkably inhibited in a dose-dependent manner in vitro. The synergistic effect of the SCS and caffeine combination could decrease the total weight of white adipose tissue by 52% compared with high-fat diet-treated group. SCS could prolong caffeine action time, and the combination of the two substances exhibited joint action on high-fat diet-induced obese mice. These findings might provide a basis for the development of functional foods and potential application using the combination of SCS and caffeine. © 2022 Society of Chemical Industry.