Acetyl-CoA carboxylase 2 mutant mice are protected against obesity and diabetes induced by high-fat/high-carbohydrate diets

Hepatic fat accumulation resulting from increased de novo fatty acid synthesis leads to hepatic steatosis and hepatic insulin resistance. We have shown previously that acetyl-CoA carboxylase 2 (Acc2−/−) mutant mice, when fed a high-fat (HF) or high-fat, high-carbohydrate (HFHC) diet, are protected against diet-induced obesity and maintained whole body and hepatic insulin sensitivity. To determine the effect of an ACC2 deletion on hepatic fat metabolism, we studied the regulation of the enzymes involved in the lipogenic pathway under Western HFHC dietary and de novo lipogenic conditions. After completing the HFHC regimen, Acc2−/− mutant mice were found to have lower body weight, smaller epididymal fat pads, lower blood levels of nonesterified fatty acids and triglycerides, and higher hepatic cholesterol than wild-type mice. Significant up-regulation of lipogenic enzymes and an elevation in hepatic peroxisome proliferator-activated receptor-γ (PPAR-γ) protein were found in Acc2−/− mutant mice under de novo lipogenic conditions. The increase in lipogenic enzyme levels was accompanied by up-regulation of the transcription factors, sterol regulatory element-binding proteins 1 and 2, and carbohydrate response element-binding protein. In contrast, hepatic levels of the PPAR-γ and PPAR-α proteins were significantly lower in the Acc2−/− mutant mice fed an HFHC diet. When compared with wild-type mice fed the same diet, Acc2−/− mutant mice exhibited a similar level of AKT but with a significant increase in pAKT. Hence, deleting ACC2 ameliorates the metabolic syndrome and protects against fatty liver despite increased de novo lipogenesis and dietary conditions known to induce obesity and diabetes.

Download Full-text

The role of rice bran extract on acetyl CoA carboxylase in liver of rats fed a high-fat diet

Planta Medica ◽

10.1055/s-0031-1282786 ◽

2011 ◽

Vol 77 (12) ◽

Author(s):

C Charkhonpunya ◽

S Sireeratawong ◽

S Komindr ◽

N Lerdvuthisopon

Keyword(s):

Rice Bran ◽

High Fat Diet ◽

Acetyl Coa Carboxylase ◽

High Fat ◽

Acetyl Coa ◽

Rice Bran Extract

Download Full-text

Insulin activation of lipogenesis in isolated mammary acini from lactating rats fed on a high-fat diet. Evidence that acetyl-CoA carboxylase is a site of action

Biochemical Journal ◽

10.1042/bj2420905 ◽

1987 ◽

Vol 242 (3) ◽

pp. 905-911 ◽

Cited By ~ 16

Author(s):

M R Munday ◽

D H Williamson

Keyword(s):

Glucose Uptake ◽

High Fat Diet ◽

Acetyl Coa Carboxylase ◽

High Fat ◽

Acetyl Coa ◽

Carboxylase Activity ◽

Glucose Incorporation ◽

Site Of Action ◽

A Site

Feeding lactating rats on high-fat cheese crackers in addition to laboratory chow increased the dietary intake of fat from 2 to 20% of the total weight of food eaten and decreased mammary-gland lipogenesis in vivo by approx. 50%. This lipogenic inhibition was also observed in isolated mammary acini, where it was accompanied by decreased glucose uptake. These inhibitions were completely reversed by incubation with insulin. Insulin had no effect on the rate of glucose transport into acini, nor on pyruvate dehydrogenase activity as estimated by the accumulation of pyruvate and lactate, suggesting that these are not the sites of lipogenic inhibition. Insulin stimulated the incorporation of [1-14C]acetate into lipid in acini from high-fat-fed rats. In the presence of alpha-cyanohydroxycinnamate, a potent inhibitor of mitochondrial pyruvate transport, and with glucose as the sole substrate, neither [1-14C]glucose incorporation into lipid nor glucose uptake were stimulated by insulin. Insulin did stimulate the incorporation of [1-14C]acetate into lipid in the presence of alpha-cyanohydroxycinnamate, and this was accompanied by an increase in glucose uptake by the acini. This indicated that increased glucose uptake was secondary to the stimulation of lipogenesis by insulin, which therefore must occur via activation of a step in the pathway distal to mitochondrial pyruvate transport. Insulin stimulated acetyl-CoA carboxylase activity measured in crude extracts of acini from high-fat-fed rats, restoring it to values close to those of chow-fed controls. The effects of insulin on acetyl-CoA carboxylase activity and lipogenesis were not antagonized by adrenaline or dibutyryl cyclic AMP.

Download Full-text

Mitochondrial acetyl-CoA carboxylase. Time course of mobilization/activation in liver of refed rats

Biochemical Journal ◽

10.1042/bj2600927 ◽

1989 ◽

Vol 260 (3) ◽

pp. 927-930 ◽

Cited By ~ 3

Author(s):

C R Roman-Lopez ◽

B J Shriver ◽

C R Joseph ◽

J B Allred

Keyword(s):

Time Course ◽

Maximal Activity ◽

Lag Time ◽

High Carbohydrate Diet ◽

Acetyl Coa Carboxylase ◽

Carbohydrate Diet ◽

Acetyl Coa ◽

High Carbohydrate

Fasted (48 h) rats were killed at 0, 2, 4, 6, 8, 12, 16, 20 and 24 h after they were refed on a high-carbohydrate diet. An increase in the maximal activity and quantity of cystolic acetyl-CoA carboxylase was found in liver of refed rats after a lag time of about 8 h. The increased quantity of cytosolic enzyme was attributable primarily to mobilization of mitochondrial storage forms and not to substantial increase in the rate of synthesis of acetyl-CoA carboxylase.

Download Full-text

Insulin activation of acetyl-CoA carboxylase in isolated mammary acini from lactating rats fed a high-fat diet

Biochemical Society Transactions ◽

10.1042/bst0141075 ◽

1986 ◽

Vol 14 (6) ◽

pp. 1075-1076 ◽

Cited By ~ 2

Author(s):

MICHAEL R. MUNDAY ◽

D. GRAHAME HARDIE

Keyword(s):

High Fat Diet ◽

Acetyl Coa Carboxylase ◽

High Fat ◽

Acetyl Coa

Download Full-text

Coffee polyphenols suppress diet-induced body fat accumulation by downregulating SREBP-1c and related molecules in C57BL/6J mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00441.2010 ◽

2011 ◽

Vol 300 (1) ◽

pp. E122-E133 ◽

Cited By ~ 130

Author(s):

Takatoshi Murase ◽

Koichi Misawa ◽

Yoshihiko Minegishi ◽

Masafumi Aoki ◽

Hideo Ominami ◽

...

Keyword(s):

Body Fat ◽

High Fat Diet ◽

Active Form ◽

Pyruvate Dehydrogenase Kinase ◽

Liver Fat ◽

Mrna Levels ◽

Acetyl Coa Carboxylase ◽

High Fat ◽

Acetyl Coa ◽

Fat Accumulation

The prevalence of obesity is increasing globally, and obesity is a major risk factor for type 2 diabetes and cardiovascular disease. We investigated the effects of coffee polyphenols (CPP), which are abundant in coffee and consumed worldwide, on diet-induced body fat accumulation. C57BL/6J mice were fed either a control diet, a high-fat diet, or a high-fat diet supplemented with 0.5 to 1.0% CPP for 2–15 wk. Supplementation with CPP significantly reduced body weight gain, abdominal and liver fat accumulation, and infiltration of macrophages into adipose tissues. Energy expenditure evaluated by indirect calorimetry was significantly increased in CPP-fed mice. The mRNA levels of sterol regulatory element-binding protein (SREBP)-1c, acetyl-CoA carboxylase-1 and -2, stearoyl-CoA desaturase-1, and pyruvate dehydrogenase kinase-4 in the liver were significantly lower in CPP-fed mice than in high-fat control mice. Similarly, CPP suppressed the expression of these molecules in Hepa 1–6 cells, concomitant with an increase in microRNA-122. Structure-activity relationship studies of nine quinic acid derivatives isolated from CPP in Hepa 1–6 cells suggested that mono- or di-caffeoyl quinic acids (CQA) are active substances in the beneficial effects of CPP. Furthermore, CPP and 5-CQA decreased the nuclear active form of SREBP-1, acetyl-CoA carboxylase activity, and cellular malonyl-CoA levels. These findings indicate that CPP enhances energy metabolism and reduces lipogenesis by downregulating SREBP-1c and related molecules, which leads to the suppression of body fat accumulation.

Download Full-text

Alterations in nutritional status regulate acetyl-CoA carboxylase expression in avian liver by a transcriptional mechanism

Biochemical Journal ◽

10.1042/bj3190263 ◽

1996 ◽

Vol 319 (1) ◽

pp. 263-268 ◽

Cited By ~ 42

Author(s):

F. Bradley HILLGARTNER ◽

Tina CHARRON ◽

Kye A CHESNUT

Keyword(s):

Fold Increase ◽

Pectoral Muscle ◽

Acetyl Coa Carboxylase ◽

Low Fat ◽

Acetyl Coa ◽

High Carbohydrate ◽

Low Fat Diet ◽

Carbohydrate Feeding ◽

Low Carbohydrate ◽

Induced Changes

Feeding previously starved chicks with a high-carbohydrate, low-fat diet stimulates a 9-fold increase in both the rate of synthesis of acetyl-CoA carboxylase (ACC) and the abundance of its mRNA in liver. To define the steps involved in mediating diet-induced changes in the abundance of ACC mRNA, transcriptional activity was measured with the nuclear run-on assay and multiple DNA probes specific to the ACC gene. ACC transcription was low in livers of starved chicks; feeding them with a high-carbohydrate, low-fat diet induced ACC transcription, increasing it 11-fold. An increase in transcription was detectable at 1 h, was maximal at 5 h and remained high for 26 h. Feeding previously starved chicks with a low-carbohydrate, high-fat diet stimulated a smaller increase (4-fold) in the abundance of ACC mRNA and the transcription of ACC than feeding with a high-carbohydrate, low-fat diet. The half-life of ACC mRNA in liver, as estimated from the kinetics of accumulation and decay of ACC mRNA during high-carbohydrate feeding and starvation, was not changed significantly by dietary manipulation. ACC mRNA was expressed at low levels in heart, pectoral muscle, kidney and brain. The abundance of ACC mRNA in these tissues was not affected by nutritional manipulation. These results demonstrate that nutritional control of the abundance of ACC mRNA in the chicken is liver-specific and is mediated primarily by changes in the rate of transcription of the ACC gene.

Download Full-text