Zhi-Hong Yang

Chronic administration of palmitoleic acid reduces insulin resistance and hepatic lipid accumulation in KK-Ay Mice with genetic type 2 diabetes.

BackgroundStudies have demonstrated the beneficial effect of palmitoleic acid (C16:1 n-7) on reducing muscle insulin resistance and preventing beta-cell apoptosis. However, the effect of palmitoleic acid on diabetes remains to be elucidated. The aim of this study was to examine the antidiabetic effect of palmitoleic acid in KK-Ay mice, a spontaneous model for studies of obese type 2 diabetes with low insulin sensitivity.MethodsKK-Ay mice were orally administered vehicle, 300 mg/kg of palmitoleic acid, or 300 mg/kg of palmitic acid (C16:0) on a daily basis for 4 weeks.ResultsPalmitoleic acid reduced body weight increase, ameliorated the development of hyperglycemia and hypertriglyceridemia, and improved insulin sensitivity. In addition, hepatic characteristics were significantly affected, as weight of the liver and hepatic triglyceride levels were lower in the palmitoleic acid group when compared to the control (vehicle and palmitic acid groups). Oil red O staining clearly indicated reduced hepatic lipid accumulation in response to palmitoleic acid. Furthermore, palmitoleic acid down-regulated mRNA expressions of proinflammatory adipocytokine genes (TNFα and resistin) in white adipose tissue and lipogenic genes (SREBP-1, FAS, and SCD-1) in liver.ConclusionsThese results suggest that palmitoleic acid improves hyperglycemia and hypertriglyceridemia by increasing insulin sensitivity, in part owing to suppressing proinflammatory gene expressions and improving hepatic lipid metabolism in diabetic mice.

Diet high in fat and sucrose induces rapid onset of obesity-related metabolic syndrome partly through rapid response of genes involved in lipogenesis, insulin signalling and inflammation in mice

BackgroundFrequent consumption of a diet high in fat and sucrose contributes to lifestyle-related diseases. However, limited information is available regarding the short-term effects of such a diet on the onset of obesity-associated metabolic abnormalities.MethodsMale C57BL/6 J mice were divided into two groups and fed a standard chow diet (control group) or a high fat–high sucrose diet containing 21% fat and 34% sucrose (HF–HS diet group) for 2 or 4 weeks.ResultsThe HF–HS diet significantly induced body weight gain beginning at week 1 and similarly increased mesenteric white adipose tissue weight and plasma insulin levels at weeks 2 and 4. Plasma resistin levels were notably elevated after feeding with the HF–HS diet for 4 weeks. Measurement of hepatic triglycerides and Oil Red O staining clearly indicated increased hepatic lipid accumulation in response to the HF–HS diet as early as 2 weeks. Quantitative PCR analysis of liver and white adipose tissue indicated that, starting at week 2, the HF–HS diet upregulated mRNA expression from genes involved in lipid metabolism and inflammation and downregulated genes involved in insulin signalling. Although plasma cholesterol levels were also rapidly increased by the HF–HS diet, no differences were found between the control and HF–HS diet–fed animals in the expression of key genes involved in cholesterol biosynthesis.ConclusionsOur study demonstrates that the rapid onset of hepatosteatosis, adipose tissue hypertrophy and hyperinsulinemia by ingestion of a diet high in fat and sucrose may possibly be due to the rapid response of lipogenic, insulin signalling and inflammatory genes.

Beneficial Effects of Dietary Fish-Oil-Derived Monounsaturated Fatty Acids on Metabolic Syndrome Risk Factors and Insulin Resistance in Mice

The aim of this study was to elucidate the effect of fish-oil-derived monounsaturated fatty acids (MUFAs) containing large amounts of C20:1 and C22:1 isomers on metabolic disorders in mice. Male C57BL/6J mice were fed a 32% lard diet (control) or a 27% lard plus 5% saury-oil-derived MUFA diet for 6 weeks. Dietary MUFA improved insulin resistance and alleviated metabolic syndrome risk factors by reducing blood glucose and lipids. These favorable changes may be attributed to an improved adipocytokine profile. MUFA ingestion resulted in favorable changes in mRNA expression of genes involved in glucose/lipid metabolism (SCD-1, CPT1a, UCPs, and CS) as well as inflammation (MAC1, MMP3, and SAA3) and alterations in fatty acid composition. Our data suggest that marine MUFA improved glucose/lipid homeostasis and hindered the development of metabolic syndrome in obese mice.

Dietary supplementation with long-chain monounsaturated fatty acids attenuates obesity-related metabolic dysfunction and increases expression of PPAR gamma in adipose tissue in type 2 diabetic KK-Ay mice

The objective of present study was to examine the effect of long-chain monounsaturated fatty acids (LC-MUFAs) with chain lengths longer than 18 (i.e., C20:1 and C22:1 isomers combined) on obesity-related metabolic dysfunction and its molecular mechanisms. Type-2 diabetic KK-Ay mice (n = 20) were randomly assigned to the 7% soybean oil-diet group (control group) and 4% LC-MUFA concentrate-supplemented-diet group (LC-MUFA group). At 8 weeks on the diet, the results showed that plasma, liver and adipose tissue levels of C20:1 and C22:1 isomers increased significantly with LC-MUFA treatment. Supplementation with LC-MUFAs markedly reduced white fat pad weight as well as adipocyte size in the mice. The levels of plasma free fatty acids, insulin, and leptin concentration in the obese diabetic mice of the LC-MUFA group were also decreased as compared with the mice in the soybean oil-diet control group. Dietary LC-MUFAs significantly increased the mRNA expression of peroxisome proliferator-activated receptor gamma (Pparg), lipoprotein lipase (Lpl), fatty acid transport protein (Fatp), fatty acid translocase/CD36 (Cd36), as well as mRNA expression of genes involved in lipid oxidation such as carnitine palmitoyltransferase-1A (Cpt1a) and citrate synthase (Cs), and decreased the mRNA expression of inflammatory marker serum amyloid A 3 (Saa3) in the adipose tissues of diabetic mice. The results suggest that LC-MUFAs may ameliorate obesity-related metabolic dysfunction partly through increased expression of Pparg as well as its target genes, and decreased inflammatory marker expression in white adipose tissue.

Pollock oil supplementation modulates hyperlipidemia and ameliorates hepatic steatosis in mice fed a high-fat diet

BackgroundHyperlipidemia associated with obesity is closely related to the development of atherosclerosis. Both n-3 polyunsaturated fatty acids (PUFAs) and long-chain monounsaturated fatty acids (MUFAs; i.e., C20:1 and C22:1 isomers) supplementation modulate risk factors for metabolic syndrome via multiple mechanisms, including the restoration of impaired lipid metabolism. We therefore examined the effects of pollock oil, which contains a considerable amount of n-3 PUFAs as well as long-chain MUFAs, on plasma hyperlipidemia and hepatic steatosis in diet-induced obese mice.MethodsMale C57BL/6J mice (24-26 g) were divided into two groups (n = 10/group) and were fed a high-fat diet containing 32% lard (control group) or 17% lard plus 15% pollock oil (experimental group) for 6 weeks. For both groups, fat comprised 60% of the total caloric intake.ResultsAlthough body and liver masses for the two groups did not differ significantly, hepatic lipids concentrations (triglycerides and total cholesterols) were lower (P < 0.05) after pollock oil ingestion. After 2 weeks on the specified diets, plasma lipid levels (total cholesterol, LDL cholesterol, and triglycerides) significantly decreased (P < 0.05) in the experimental group compared with the control group, although plasma HDL cholesterol levels did not differ. At the end of 6 weeks, plasma adiponectin levels increased (P < 0.05), whereas plasma resistin and leptin levels decreased (P < 0.05) in the experimental mice. Increased levels of long-chain MUFAs and n-3 PUFAs in plasma, liver and adipose tissue by ingesting pollock oil were possibly correlated to these favorable changes. Expression of hepatic genes involved in cholesterol metabolism (SREBP2, HMGCR, and ApoB) and lipogenesis (SREPB1c, SCD-1, FAS, and Acac α) was suppressed in the experimental group, and may have favorably affected hyperlipidemia and hepatic steatosis induced by the high-fat diet.ConclusionsWe demonstrated that pollock oil supplementation effectively improved hyperlipidemia, attenuated hepatic steatosis, and downregulated the express of hepatic genes involved in cholesterol and lipid metabolism in mice with diet-induced obesity.

Oral administration of omega-7 palmitoleic acid induces satiety and the release of appetite-related hormones in male rats.

We have analyzed the effect of palmitoleic acid on short-term food intake in male rats. Administration of omega-7 palmitoleic acid by oral gavage significantly decreased food intake compared to palmitic acid, omega-9 oleic acid, or a vehicle control. Palmitoleic acid exhibited a dose-dependent effect in this context and did not cause general malaise. A triglyceride form of palmitoleate also decreased food intake, whereas olive oil, which is rich in oleic acid, did not. Palmitoleic acid accumulated within the small intestine in a dose-dependent fashion and elevated levels of the satiety hormone cholecystokinin (CCK). Both protein and mRNA levels of CCK were affected in this context. The suppression of food intake by palmitoleic acid was attenuated by intravenous injection of devazepide, a selective peripheral CCK receptor antagonist. Palmitoleic acid did not alter the expression of peroxisome proliferator-activated receptor alpha (PPARα) target genes, and a PPARα antagonist did not affect palmitoleic acid-induced satiety. This suggests that the PPARα pathway might not be involved in suppressing food intake in response to palmitoleic acid. We have shown that orally administered palmitoleic acid induced satiety, enhanced the release of satiety hormones in rats.

Dietary marine-derived long-chain monounsaturated fatty acids and cardiovascular disease risk: a mini review

Regular fish/fish oil consumption is widely recommended for protection against cardiovascular diseases (CVD). Fish and other marine life are rich sources of the cardioprotective long-chain n-3 polyunsaturated fatty acids (n-3 PUFA) eicosapentaenoic acid (C20:5 n-3; EPA) and docosahexaenoic acid (C22:6 n-3; DHA). The lipid content and fatty acid profile of fish, however, vary greatly among different fish species. In addition to n-3 PUFA, certain fish, such as saury, pollock, and herring, also contain high levels of long-chain monounsaturated fatty acids (LCMUFA), with aliphatic tails longer than 18 C atoms (i.e., C20:1 and C22:1 isomers). Compared with well-studied n-3 PUFA, limited information, however, is available on the health benefits of marine-derived LCMUFA, particularly in regard to CVD. Our objective in this review is to summarize the current knowledge and provide perspective on the potential therapeutic value of dietary LCMUFA-rich marine oil for improving CVD risk factors. We will also review the possible mechanisms of LCMUFA action on target tissues. Finally, we describe the epidemiologic data and small-scaled clinical studies that have been done on marine oils enriched in LCMUFA. Although there are still many unanswered questions about LCMUFA, this appears to be promising new area of research that may lead to new insights into the health benefits of a different component of fish oils besides n-3 PUFA.

Long‐chain monounsaturated fatty acid‐rich fish oil attenuates the development of atherosclerosis in mouse models

SCOPE Fish oil-derived long-chain monounsaturated fatty acids (LCMUFA) containing chain lengths longer than 18 were previously shown to improve cardiovascular disease risk factors in mice. However, it is not known if LCMUFA also exerts anti-atherogenic effects. The main objective of the present study was to investigate the effect of LCMUFA on the development of atherosclerosis in mouse models. METHODS AND RESULTS LDLR-KO mice were fed Western diet supplemented with 2% (w/w) of either LCMUFA concentrate, olive oil, or not (control) for 12 wk. LCMUFA, but not olive oil, significantly suppressed the development of atherosclerotic lesions and several plasma inflammatory cytokine levels, although there were no major differences in plasma lipids between the three groups. At higher doses 5% (w/w) LCMUFA supplementation was observed to reduce pro-atherogenic plasma lipoproteins and to also reduce atherosclerosis in ApoE-KO mice fed a Western diet. RNA sequencing and subsequent qPCR analyses revealed that LCMUFA upregulated PPAR signaling pathways in liver. In cell culture studies, apoB-depleted plasma from LDLR-K mice fed LCMUFA showed greater cholesterol efflux from macrophage-like THP-1 cells and ABCA1-overexpressing BHK cells. CONCLUSION Our research showed for the first time that LCMUFA consumption protects against diet-induced atherosclerosis, possibly by upregulating the PPAR signaling pathway.

Addition of aspirin to a fish oil-rich diet decreases inflammation and atherosclerosis in ApoE-null mice.

Aspirin (ASA) is known to alter the production of potent inflammatory lipid mediators, but whether it interacts with omega-3 fatty acids (FAs) from fish oil to affect atherosclerosis has not been determined. The goal was to investigate the impact of a fish oil-enriched diet alone and in combination with ASA on the production of lipid mediators and atherosclerosis. ApoE(-/-) female mice were fed for 13weeks one of the four following diets: omega-3 FA deficient (OD), omega-3 FA rich (OR) (1.8g omega-3 FAs/kg·diet per day), omega-3 FA rich plus ASA (ORA) (0.1g ASA/kg·diet per day) or an omega-3 FA deficient plus ASA (ODA) with supplement levels equivalent to human doses. Plasma lipids, atherosclerosis, markers of inflammation, hepatic gene expression and aortic lipid mediators were determined. Hepatic omega-3 FAs were markedly higher in OR (9.9-fold) and ORA (7-fold) groups. Mice in both OR and ORA groups had 40% less plasma cholesterol in very low-density lipoprotein-cholesterol and low-density lipoprotein fractions, but aortic plaque area formation was only significantly lower in the ORA group (5.5%) compared to the OD group (2.5%). Plasma PCSK9 protein levels were approximately 70% lower in the OR and ORA groups. Proinflammatory aortic lipid mediators were 50%-70% lower in the ODA group than in the OD group and more than 50% lower in the ORA group. In summary, less aortic plaque lesions and aortic proinflammatory lipid mediators were observed in mice on the fish oil diet plus ASA vs. just the fish oil diet.

Dietary α‐cyclodextrin reduces atherosclerosis and modifies gut flora in apolipoprotein E‐deficient mice

SCOPE α-Cyclodextrin (α-CD), a cyclic polymer of glucose, has been shown to lower plasma cholesterol in animals and humans; however, its effect on atherosclerosis has not been previously described. METHODS AND RESULTS apoE-knockout mice were fed either low-fat diet (LFD; 5.2% fat, w/w), or Western high fat diet (21.2% fat) containing either no additions (WD), 1.5% α-CD (WDA); 1.5% β-CD (WDB); or 1.5% oligofructose-enriched inulin (WDI). Although plasma lipids were similar after 11 weeks on the WD vs. WDA diets, aortic atherosclerotic lesions were 65% less in mice on WDA compared to WD (P < 0.05), and similar to mice fed the LFD. No effect on atherosclerosis was observed for the other WD supplemented diets. By RNA-seq analysis of 16S rRNA, addition of α-CD to the WD resulted in significantly decreased cecal bacterial counts in genera Clostridium and Turicibacterium, and significantly increased Dehalobacteriaceae. At family level, Comamonadaceae significantly increased and Peptostreptococcaceae showed a negative trend. Several of these bacterial count changes correlated negatively with % atherosclerotic lesion and were associated with increased cecum weight and decreased plasma cholesterol levels. CONCLUSION Addition of α-CD to the diet of apoE-knockout mice decreases atherosclerosis and is associated with changes in the gut flora.