A Novel Micronutrient Supplement to Preserve Male Metabolic Health and Prevent Fatty Liver (P21-007-19)

Abstract Objectives Growing evidence shows detrimental effects of paternal obesity on subsequent generations. We designed a micronutrient supplement whose components participate in one carbon metabolism and are anticipated to improve antioxidant capacity. Here, we studied the effects of the supplement on metabolic health and hepatic lipid metabolism in male rats consuming either a normal healthy diet or an obesogenic diet. Methods Male Sprague Dawley rats (3 weeks old, 17/group) were weaned onto control (CD) or high fat diet (HFD) with or without added micronutrient supplement (CDS; HFDS). After 12 weeks of diet, body composition was measured by magnetic resonance imaging, and blood samples were collected to assess supplementation levels. After 19 weeks of diet, oral glucose tolerance test (OGTT) was performed and plasma was collected to determine insulin release. At 27 weeks of diet, the rats were fasted and culled to harvest blood and tissues. Liver lipids and expression of genes involved in hepatic development and lipid metabolism were measured. Results Supplementation was confirmed by determining plasma folate concentrations (one component of supplement), which were increased by 26% across supplemented groups. HFD increased adiposity (P < 0.001) and body weight (P < 0.001), both of which were normalized in the HFDS group. HFD fed animals were glucose intolerant (blood glucose during OGTT, P = 0.005) compared to CD fed animals and had to release more insulin to clear an equivalent glucose load (insulin release during OGTT, P < 0.001). In comparison, the animals consuming HFDS needed less insulin to clear an equivalent glucose load (P < 0.001 vs HFD). HFD rats had larger livers than HFDS rats (P < 0.001). Micronutrient supplementation reduced hepatic triglyceride accumulation (P < 0.001) regardless of diet; this was accompanied by altered gene expression (particularly of CPT-1). Conclusions Dietary micronutrient supplementation prevented weight gain and adiposity, improved metabolic health, and excess lipid accumulation in liver in response to HFD. This provides evidence that the micronutrient supplement can preserve health and prevent fatty liver even when animals consume an obesogenic diet. Funding Sources NHMRC Australia project grant held by MJM and CAM. SK was supported by a UNSW international scholarship.

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Effects of Micronutrient Supplementation on Glucose and Hepatic Lipid Metabolism in a Rat Model of Diet Induced Obesity

Cells ◽

10.3390/cells10071751 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1751

Author(s):

Saroj Khatiwada ◽

Virginie Lecomte ◽

Michael F. Fenech ◽

Margaret J. Morris ◽

Christopher A. Maloney

Keyword(s):

Insulin Resistance ◽

Lipid Metabolism ◽

Glucose Tolerance ◽

Antioxidant Capacity ◽

Fasting Glucose ◽

Oral Glucose ◽

Model Assessment ◽

Micronutrient Supplementation ◽

Sprague Dawley ◽

Triglyceride Accumulation

Obesity increases the risk of metabolic disorders, partly through increased oxidative stress. Here, we examined the effects of a dietary micronutrient supplement (consisting of folate, vitamin B6, choline, betaine, and zinc) with antioxidant and methyl donor activities. Male Sprague Dawley rats (3 weeks old, 17/group) were weaned onto control (C) or high-fat diet (HFD) or same diets with added micronutrient supplement (CS; HS). At 14.5 weeks of age, body composition was measured by magnetic resonance imaging. At 21 weeks of age, respiratory quotient and energy expenditure was measured using Comprehensive Lab Animal Monitoring System. At 22 weeks of age, an oral glucose tolerance test (OGTT) was performed, and using fasting glucose and insulin values, Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) was calculated as a surrogate measure of insulin resistance. At 30.5 weeks of age, blood and liver tissues were harvested. Liver antioxidant capacity, lipids and expression of genes involved in lipid metabolism (Cd36, Fabp1, Acaca, Fasn, Cpt1a, Srebf1) were measured. HFD increased adiposity (p < 0.001) and body weight (p < 0.001), both of which did not occur in the HS group. The animals fed HFD developed impaired fasting glucose, impaired glucose tolerance, and fasting hyperinsulinemia compared to control fed animals. Interestingly, HS animals demonstrated an improvement in fasting glucose and fasting insulin. Based on insulin release during OGTT and HOMA-IR, the supplement appeared to reduce the insulin resistance developed by HFD feeding. Supplementation increased hepatic glutathione content (p < 0.05) and reduced hepatic triglyceride accumulation (p < 0.001) regardless of diet; this was accompanied by altered gene expression (particularly of CPT-1). Our findings show that dietary micronutrient supplementation can reduce weight gain and adiposity, improve glucose metabolism, and improve hepatic antioxidant capacity and lipid metabolism in response to HFD intake.

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Preabsorptive insulin release and hypoglycemia in rats

American Journal of Physiology-Legacy Content ◽

10.1152/ajplegacy.1976.230.1.56 ◽

1976 ◽

Vol 230 (1) ◽

pp. 56-60 ◽

Cited By ~ 155

Author(s):

J Louis-Sylvestre

Keyword(s):

Blood Glucose ◽

Insulin Release ◽

Oral Intake ◽

Hypothalamic Nucleus ◽

Oral Glucose ◽

Glucose Load ◽

Glucose Intake ◽

Metabolic Conditions ◽

Freely Moving ◽

Two Peaks

Peripheral blood glucose and immunologically reactive insulin levels were determined in freely moving normal rats which were submitted either to a free oral glucose load or to a gastric administration of the glucose load. Identical determinations were performed in ventromedial hypothalamic nucleus-(VMH) lesioned and vagotomized rats after the same oral intake. It was demonstrated that: 1) a free oral glucose intake was immediately followed by two peaks of insulun release and a resultant decrease in blood glucose; 2) a gastric glucose load resulted in a single peak of insulin release and the concomitant decline in blood glucose; 3) the recorded blood glucose level was the resultant of the insulin-induced hypoglycemia and the postabsorptive hyperglycemia; and 4) the responses were largely exaggerated in VMH-lesioned rats and abolished by vagotomy. It is concluded that the early prandial insulin release reflexly induced by food-related stimuli temporarily enhances the metabolic conditions which provoke feeding.

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Pre-β1-lipoprotein and Lp(a) Antigen in Relation to Triglyceride Levels and Insulin Release Following an Oral Glucose Load in Middle-aged Males

Acta Medica Scandinavica ◽

10.1111/j.0954-6820.1976.tb06757.x ◽

2009 ◽

Vol 199 (1-6) ◽

pp. 413-420 ◽

Cited By ~ 7

Author(s):

Gösta Dahlén ◽

Kåre Berg

Keyword(s):

Insulin Release ◽

Oral Glucose ◽

Oral Glucose Load ◽

Glucose Load ◽

Middle Aged

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Kupffer cell depletion protects against the steatosis, but not the liver damage, induced by marginal-copper, high-fructose diet in male rats

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00285.2014 ◽

2015 ◽

Vol 308 (11) ◽

pp. G934-G945 ◽

Cited By ~ 8

Author(s):

Ming Song ◽

Dale A. Schuschke ◽

Zhanxiang Zhou ◽

Wei Zhong ◽

Jiayuan Zhang ◽

...

Keyword(s):

Fatty Liver ◽

Regulatory Element ◽

Critical Role ◽

Deionized Water ◽

Male Rats ◽

Sprague Dawley ◽

Deficient Diet ◽

High Fructose Diet ◽

Triglyceride Accumulation ◽

High Fructose

High-fructose feeding impairs copper status and leads to low copper availability, which is a novel mechanism in obesity-related fatty liver. Copper deficiency-associated hepatic iron overload likely plays an important role in fructose-induced liver injury. Excess iron in the liver is distributed throughout hepatocytes and Kupffer cells (KCs). The aim of this study was to examine the role of KCs in the pathogenesis of nonalcoholic fatty liver disease induced by a marginal-copper high-fructose diet (CuMF). Male weanling Sprague-Dawley rats were fed either a copper-adequate or a marginally copper-deficient diet for 4 wk. Deionized water or deionized water containing 30% fructose (wt/vol) was also given ad libitum. KCs were depleted by intravenous administration of gadolinium chloride (GdCl3) before and/or in the middle of the experimental period. Hepatic triglyceride accumulation was completely eliminated with KC depletion in CuMF consumption rats, which was associated with the normalization of elevated plasma monocyte chemoattractant protein-1 (MCP-1) and increased hepatic sterol regulatory element binding protein-1 expression. However, hepatic copper and iron content were not significantly affected by KC depletion. In addition, KC depletion reduced body weight and epididymal fat weight as well as adipocyte size. Plasma endotoxin and gut permeability were markedly increased in CuMF rats. Moreover, MCP-1 was robustly increased in the culture medium when isolated KCs from CuMF rats were treated with LPS. Our data suggest that KCs play a critical role in the development of hepatic steatosis induced by marginal-copper high-fructose diet.

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Study of Glucose and Lipid Metabolism by Continuous Indirect Calorimetry in Graves’ Disease: Effect of an Oral Glucose Load

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem-61-6-1165 ◽

1985 ◽

Vol 61 (6) ◽

pp. 1165-1171 ◽

Cited By ~ 22

Author(s):

J. P. RANDIAN ◽

E. JEQUIER ◽

J. P. FELBER

Keyword(s):

Lipid Metabolism ◽

Indirect Calorimetry ◽

Oral Glucose ◽

Graves Disease ◽

Oral Glucose Load ◽

Glucose Load ◽

Glucose And Lipid Metabolism ◽

Disease Effect

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Fructo-Oligosaccharides and Pectins Enhance Beneficial Effects of Raspberry Polyphenols in Rats with Nonalcoholic Fatty Liver

Nutrients ◽

10.3390/nu13030833 ◽

2021 ◽

Vol 13 (3) ◽

pp. 833

Author(s):

Bartosz Fotschki ◽

Jerzy Juśkiewicz ◽

Adam Jurgoński ◽

Michał Sójka

Keyword(s):

Lipid Metabolism ◽

Fatty Liver ◽

Liver Lipid ◽

Dietary Treatment ◽

Short Chain Fatty Acids ◽

Liver Fat ◽

Nonalcoholic Fatty Liver ◽

Polyphenolic Extract ◽

Obesogenic Diet ◽

Liver Lipid Metabolism

In recent years, nonalcoholic fatty liver disorders have become one of the most common liver pathologies; therefore, it is necessary to investigate the dietary compounds that may support the regulation of liver metabolism and related inflammatory processes. The present study examines the effect of raspberry polyphenolic extract (RE) combined with fructo-oligosaccharides (FOSs) or pectins (PECs) on caecal microbial fermentation, liver lipid metabolism and inflammation in rats with fatty liver induced by an obesogenic diet. The combination of RE with FOSs or PECs reduced the production of short-chain fatty acids in the caecum. RE combined with FOSs exerted the most favourable effects on liver lipid metabolism by decreasing liver fat, cholesterol, triglyceride content and hepatic steatosis. RE and FOSs reduced lobular and portal inflammatory cell infiltration and IL-6 plasma levels. These effects might be related to a decrease in the hepatic expressions of PPARγ and ANGPTL4. In conclusion, PECs and FOSs enhanced the effects of RE against disorders related to nonalcoholic fatty liver; however, the most effective dietary treatment in the regulation of liver lipid metabolism and inflammation caused by an obesogenic diet was the combination of RE with FOSs.

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Maternal Obesogenic Diet Regulates Offspring Bile Acid Homeostasis and Hepatic Lipid Metabolism via the Gut Microbiome in Mice

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00247.2021 ◽

2022 ◽

Author(s):

Michael D. Thompson ◽

Jisue Kang ◽

Austin Faerber ◽

Holly Hinrichs ◽

Oguz Ozler ◽

...

Keyword(s):

Lipid Metabolism ◽

Bile Acid ◽

Mrna Expression ◽

16S Sequencing ◽

Hepatic Expression ◽

Lipogenic Genes ◽

Triglyceride Accumulation ◽

High Fructose ◽

Obesogenic Diet ◽

Donor Offspring

Mice exposed in gestation to maternal high fat/high sucrose (HF/HS) diet develop altered bile acid (BA) homeostasis. We hypothesized that these reflect an altered microbiome and asked if microbiota transplanted from HF/HS offspring change hepatic BA and lipid metabolism to determine the directionality of effect. Female mice were fed HF/HS or chow (CON) for 6 weeks and bred with lean males. 16S sequencing was performed to compare taxa in offspring. Cecal microbiome transplantation (CMT) was performed from HF/HS or CON offspring into antibiotic treated mice fed chow or high fructose. BA, lipid metabolic, and gene expression analyses performed in recipient mice. Gut microbiomes from HF/HS offspring segregated from CON offspring, with increased Firmicutes to Bacteriodetes ratios and Verrucomicrobial abundance. Following CMT, HF/HS recipient mice had larger BA pools, and increased intrahepatic muricholic acid and decreased deoxycholic acid species. HF/HS recipient mice exhibited downregulated hepatic Mrp2, increased hepatic Oatp1b2, and decreased ileal Asbt mRNA expression. HF/HS recipient mice exhibited decreased cecal butyrate and increased hepatic expression of Il6. HF/HS recipient mice had larger livers, and increased intrahepatic triglyceride versus CON recipient mice after fructose feeding, with increased hepatic mRNA expression of lipogenic genes including Srebf1, Fabp1, Mogat1, and Mogat2. CMT from HF/HS offspring increased BA pool and shifted the composition of the intrahepatic BA pool. CMT from HF/HS donor offspring increased fructose-induced liver triglyceride accumulation. These findings support a causal role for vertical transfer of an altered microbiome in hepatic BA and lipid metabolism in HF/HS offspring.

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