Impaired Coordination of Nutrient Intake and Substrate Oxidation in Melanocortin-4 Receptor Knockout Mice

Albarado, Diana C.; McClaine, Jennifer W.; Stephens, Jacqueline M.; Mynatt, Randall L.; Ye, Jianping; Bannon, Anthony W.; Richards, William G.; Butler, Andrew A.

doi:10.1210/en.2003-0452

Cited by 92 publications

(100 citation statements)

References 51 publications

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“…In essence, these observations are consistent with previous reports that described the metabolic phenotypes in the liver in MC4R-KO mice, which were generated using different strategies. 18,19 Collectively, our data indicate that MC4R-KO mice fed …”

Section: Metabolic Phenotypes Of Mc4r-ko Micementioning

confidence: 56%

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Melanocortin 4 Receptor–Deficient Mice as a Novel Mouse Model of Nonalcoholic Steatohepatitis

Ichii

Suganami

Nakagawa

et al. 2011

The American Journal of Pathology

144

149

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Obesity may be viewed as a state of chronic low-grade inflammation that participates in the development of the metabolic syndrome. Nonalcoholic steatohepatitis (NASH) is considered a hepatic phenotype of the metabolic syndrome and a high risk for progression to cirrhosis and hepatocellular carcinoma. Although the "two hit" hypothesis suggests involvement of excessive hepatic lipid accumulation and chronic inflammation, the molecular mechanisms underlying the development of NASH remain unclear, in part because of lack of appropriate animal models. Herein we report that melanocortin 4 receptor-deficient mice (MC4R-KO) develop steatohepatitis when fed a high-fat diet, which is associated with obesity, insulin resistance, and dyslipidemia. Histologic analysis reveals inflammatory cell infiltration, hepatocyte ballooning, and pericellular fibrosis in the liver in MC4R-KO mice. Of note, all of the MC4R-KO mice examined developed well-differentiated hepatocellular carcinoma after being fed a high-fat diet for 1 year. They also demonstrated enhanced adipose tissue inflammation, ie, increased macrophage infiltration and fibrotic changes, which may contribute to excessive lipid accumulation and enhanced fibrosis in the liver. Thus, MC4R-KO mice provide a novel mouse model of NASH with which to investigate the sequence of events that make up diet-induced hepatic steatosis, liver fibrosis, and hepatocellular carcinoma and to aid in understanding the pathogenesis of NASH, pursuing specific biomarkers, and evaluating Nonalcoholic fatty liver disease (NAFLD) is characterized by increased accumulation of lipids in the liver without a history of excessive alcohol consumption or known liver disease.1 NAFLD often occurs with the metabolic syndrome, a constellation of visceral fat obesity, impaired glucose metabolism, atherogenic dyslipidemia, and elevated blood pressure, and is considered the hepatic manifestation of the metabolic syndrome.2 Patients with nonalcoholic steatohepatitis (NASH), a subset of NAFLD, are at high risk for progression to cirrhosis and hepatocellular carcinoma (HCC). However, the molecular mechanisms involved in disease progression from simple steatosis to NASH to HCC are currently unclear. This is in part because there are no appropriate animal models that reflect a liver condition of human NASH, although many attempts have been made to generate animal NASH models via genetic, dietary, and pharmacologic approaches. 3The pathogenesis of NASH is thought to involve a multistep process in which the first step is excessive accumulation of lipids in the liver. According to the "two hit" hypothesis, the development of NASH requires the presence of additional pathogenic factors such as oxidative stress, endotoxins, cytokines, chemokines, and lipotoxicity. 4 -6 Because NASH is often associated with visceral fat obesity, there should be a mechanistic link

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Section: Metabolic Phenotypes Of Mc4r-ko Micementioning

confidence: 56%

“…16,17 MC4R-deficient mice (MC4R-KO mice) fed a high-fat diet (HFD) exhibit massive hepatic steatosis and altered gene expression related to lipid metabolism. 18,19 The role of MC4R in the pathogenesis of NASH, however, has not been elucidated.…”

mentioning

confidence: 99%

Melanocortin 4 Receptor–Deficient Mice as a Novel Mouse Model of Nonalcoholic Steatohepatitis

Ichii

Suganami

Nakagawa

et al. 2011

The American Journal of Pathology

144

149

View full text Add to dashboard Cite

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“…Tissue processing and isolated muscle experiments are described in SI Materials and Methods. Indirect calorimetry was done in a 16-chamber Oxymax system (Columbus Instruments) as described by Albarado et al (40). Behavioral studies were performed with slight modifications from the method of Wicks et al (41).…”

Section: Methodsmentioning

confidence: 99%

Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism

Wicks

Vandanmagsar

Haynie

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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107

134

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The correlations between intramyocellular lipid (IMCL), decreased fatty acid oxidation (FAO), and insulin resistance have led to the hypothesis that impaired FAO causes accumulation of lipotoxic intermediates that inhibit muscle insulin signaling. Using a skeletal muscle-specific carnitine palmitoyltransferase-1 KO model, we show that prolonged and severe mitochondrial FAO inhibition results in increased carbohydrate utilization, along with reduced physical activity; increased circulating nonesterified fatty acids; and increased IMCLs, diacylglycerols, and ceramides. Perhaps more importantly, inhibition of mitochondrial FAO also initiates a local, adaptive response in muscle that invokes mitochondrial biogenesis, compensatory peroxisomal fat oxidation, and amino acid catabolism. Loss of its major fuel source (lipid) induces an energy deprivation response in muscle coordinated by signaling through AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) to maintain energy supply for locomotion and survival. At the whole-body level, these adaptations result in resistance to obesity.carnitine palmitoyltransferase | muscle | fatty acid | lipid | carbohydrate C onsiderable evidence suggests that when oversupply of dietary fat exceeds the storage capacity of adipose tissue, ectopic lipids accumulate in skeletal muscle, leading to "metabolic stress" that induces insulin resistance. One prevailing theory is that impaired skeletal muscle fatty acid oxidation (FAO) (1-4) leads to cytosolic accumulation of lipotoxic intermediates that are directly linked to defects in insulin signaling (5-11). Recent findings counter this premise because they have shown that models of insulin resistance consistently exhibit enhanced (not reduced) FAO, as demonstrated by elevated incomplete β-oxidation and accumulation of excess lipid-derived acylcarnitines (12, 13). Supporting evidence was obtained using a whole-body genetic approach to elevate levels of the endogenous carnitine palmitoyltransferase-1 (Cpt1) inhibitor, malonyl-CoA (12). These studies have led to the contrasting theory that lipid overload and incomplete FAO within the mitochondria accelerate the progression of insulin resistance (14). Faced with a plethora of studies supporting both hypotheses, a crucial question remains: "Is inhibition of mitochondrial FAO in skeletal muscle sufficient to initiate development of insulin resistance?" Cpt1 is essential for long-chain acyl-CoA transport into the mitochondria, and lies at the nexus of both the lipotoxicity and the mitochondrial overload hypotheses. If decreased FAO is a root cause of lipotoxicity, then muscle-specific ablation of Cpt1b activity should lead to impaired FAO, intramyocellular lipid (IMCL) accumulation, and insulin resistance. In stark contrast, the mitochondrial overload hypothesis suggests that decreased Cpt1b activity would preserve insulin sensitivity by preventing unbalanced overfueling of β-oxidation. Characterization of the rare genetic disorders o...

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“…During this time, food intake and body weight were measured every other day and body composition was measured weekly. Indirect calorimetry was then performed as previously described [17] using a 16-chamber Oxymax system (Columbus Instruments, Columbus, OH, USA). Mice were acclimatised to the system for 3 days prior to measurement.…”

Section: Methodsmentioning

confidence: 99%

Carnitine revisited: potential use as adjunctive treatment in diabetes

et al. 2007

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Aims/hypothesis This study examined the efficacy of supplemental L-carnitine as an adjunctive diabetes therapy in mouse models of metabolic disease. We hypothesised that carnitine would facilitate fatty acid export from tissues in the form of acyl-carnitines, thereby alleviating lipidinduced insulin resistance. Materials and methods Obese mice with genetic or dietinduced forms of insulin resistance were fed rodent chow ± 0.5% L-carnitine for a period of 1-8 weeks. Metabolic outcomes included insulin tolerance tests, indirect calorimetry and mass spectrometry-based profiling of acyl-carnitine esters in tissues and plasma.Results Carnitine supplementation improved insulin-stimulated glucose disposal in genetically diabetic mice and wild-type mice fed a high-fat diet, without altering body weight or food intake. In severely diabetic mice, carnitine supplementation increased average daily respiratory exchange ratio from 0.886±0.01 to 0.914±0.01 (p<0.01), reflecting a marked increase in systemic carbohydrate oxidation. Similarly, under insulin-stimulated conditions, carbohydrate oxidation was higher and total energy expenditure increased from 172±10 to 210±9 kJ kg fatfree mass −1 h −1 in the carnitine-supplemented compared with control animals. These metabolic improvements corresponded with a 2.3-fold rise in circulating levels of acetyl-carnitine, which accounts for 86 and 88% of the total acyl-carnitine pool in plasma and skeletal muscle, respectively. Carnitine supplementation also increased several medium-and long-chain acyl-carnitine species in both plasma and tissues. Conclusions/interpretation These findings suggest that carnitine supplementation relieves lipid overload and glucose intolerance in obese rodents by enhancing mitochondrial efflux of excess acyl groups from insulin-responsive tissues. Carefully controlled clinical trials should be considered.

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Impaired Coordination of Nutrient Intake and Substrate Oxidation in Melanocortin-4 Receptor Knockout Mice

Cited by 92 publications

References 51 publications

Melanocortin 4 Receptor–Deficient Mice as a Novel Mouse Model of Nonalcoholic Steatohepatitis

Melanocortin 4 Receptor–Deficient Mice as a Novel Mouse Model of Nonalcoholic Steatohepatitis

Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism

Carnitine revisited: potential use as adjunctive treatment in diabetes

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