Metabolic flexibility and insulin resistance

Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808, USA.
AJP Endocrinology and Metabolism (Impact Factor: 3.79). 08/2008; 295(5). DOI: 10.1152/ajpendo.90558.2008
Source: OAI


Metabolic flexibility is the capacity for the organism to adapt fuel oxidation to fuel availability. The inability to modify fuel oxidation in response to changes in nutrient availability has been implicated in the accumulation of intramyocellular lipid and insulin resistance. The metabolic flexibility assessed by the ability to switch from fat to carbohydrate oxidation is usually impaired during a hyperinsulinemic clamp in insulin-resistant subjects; however, this "metabolic inflexibility" is mostly the consequence of impaired cellular glucose uptake. Indeed, after controlling for insulin-stimulated glucose disposal rate ( amount of glucose available for oxidation), metabolic flexibility is not altered in obesity regardless of the presence of type 2 diabetes. To understand how intramyocellular lipids accumulate and cause insulin resistance, the assessment of metabolic flexibility to high-fat diets is more relevant than metabolic flexibility during a hyperinsulinemic clamp. An impaired capacity to upregulate muscle lipid oxidation in the face of high lipid supply may lead to increased muscle fat accumulation and insulin resistance. Surprisingly, very few studies have investigated the response to high-fat diets. In this review, we discuss the role of glucose disposal rate, adipose tissue lipid storage, and mitochondrial function on metabolic flexibility. Additionally, we emphasize the bias of using the change in respiratory quotient to calculate metabolic flexibility and propose novel approaches to assess metabolic flexibility. On the basis of current evidence, one cannot conclude that impaired metabolic flexibility is responsible for the accumulation of intramyocellular lipid and insulin resistance. We propose to study metabolic flexibility in response to high- fat diets in individuals having contrasting degree of insulin sensitivity and/or mitochondrial characteristics. National Institutes of Health U01-AG-020478 RO1-DK-60412

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    • "Skeletal muscle is a major consumer of blood glucose under insulin-stimulated conditions [2] [3] and therefore plays a key role in maintaining whole-body glucose homeostasis. Obesity-related skeletal muscle insulin resistance is associated with accumulation of intramyocellular triacylglycerols (TAG), altered carbohydrate and lipid metabolism, resulting in diminished metabolic flexibility and impaired energy production [4], which, in turn, is essential for supporting normal contractile function of skeletal muscle. A number of studies employing rodent models of high-fat-diet (HFD)-induced obesity and insulin resistance have shown that, depending on the content and type of dietary fat as well as the duration of feeding, increased availability of lipids in skeletal muscle may have varying consequences for cellular energy metabolism, including upregulation of genes coding for enzymes of mitochondrial β-oxidation [5] [6], increased mitochondrial capacity to oxidize fatty acids (FAs) and stimulation of mitochondrial biogenesis [7] [8] [9], as well as altered mitochondrial morphology and compromised adenosine triphosphate (ATP) production [7] [10] [11]. "
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    ABSTRACT: High-fat diets (HFD) have been shown to interfere with skeletal muscle energy metabolism and cause peripheral insulin resistance. However, understanding of HFD impact on skeletal muscle primary function – i.e., contractile performance, is limited. Male C57BL/6 J mice were fed HFD containing lard (HFL) or palm oil (HFP), or low-fat diet (LFD) for 5 weeks. Fast-twitch (FT) extensor digitorum longus (EDL) and slow-twitch (ST) soleus muscles were characterized with respect to contractile function and selected biochemical features. In FT EDL muscle, a 30-50% increase in fatty acid (FA) content and doubling of long-chain acylcarnitine (AC) (C14-C18) content in response to HFL and HFP feeding was accompanied by increase in protein levels of peroxisome proliferator-activated receptor-γ coactivator-1α, mitochondrial oxidative phosphorylation complexes and acyl-CoA dehydrogenases involved in mitochondrial FA β-oxidation. Peak force of FT EDL twitch and tetanic contractions were unaltered but the relaxation time (RT) of twitch contractions was 30% slower compared to LFD controls. The latter was caused by accumulation of lipid intermediates rather than changes in the expression levels of proteins involved in calcium handling. In ST soleus muscle, no evidence for lipid overload was found in any HFD group. However, particularly in HFP group, the peak force of twitch and tetanic contractions were reduced but RT was faster than LFD controls. The latter was associated with a fast-to-slow shift in troponin T isoform expression. Taken together, these data highlight fiber-type specific sensitivities and phenotypic adaptations to dietary lipid overload that differentially impact fast- versus slow-twitch skeletal muscle contractile function.
    The Journal of Nutritional Biochemistry 10/2014; 26(2). DOI:10.1016/j.jnutbio.2014.09.014 · 3.79 Impact Factor
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    • "Obesity combined with oxidized lipid species compromises mitochondrial function through nonspecific modification of proteins, lipids, and nucleic acids (Gutierrez et al. 2006). Impaired mitochondrial function may be a primary cause for metabolic inflexibility (van de Weijer et al. 2013; Galgani et al. 2008). Indirect calorimetry results from our study clearly indicated that Iqgap2 -/-mice were metabolically inflexible during the fast to refed transition. "
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    ABSTRACT: Deficiency of IQGAP2, a scaffolding protein expressed primarily in liver leads to rearrangements of hepatic protein compartmentalization and altered regulation of enzyme functions predisposing development of hepatocellular carcinoma and diabetes. Employing a systems approach with proteomics, metabolomics and fluxes characterizations, we examined the effects of IQGAP2 deficient proteomic changes on cellular metabolism and the overall metabolic phenotype. Iqgap2 −/−mice demonstrated metabolic inflexibility, fasting hyperglycemia and obesity. Such phenotypic characteristics were associated with aberrant hepatic regulations of glycolysis/gluconeogenesis, glycogenolysis, lipid homeostasis and futile cycling corroborated with corresponding proteomic changes in cytosolic and mitochondrial compartments. IQGAP2 deficiency also led to truncated TCA-cycle, increased anaplerosis, increased supply of acetyl-CoA for de novo lipogenesis, and increased mitochondrial methyl-donor metabolism necessary for nucleotides synthesis. Our results suggest that changes in metabolic networks in IQGAP2 deficiency create a hepatic environment of a ‘pre-diabetic’ phenotype and a predisposition to non-alcoholic fatty liver disease which has been linked to the development of hepatocellular carcinoma.
    Metabolomics 10/2014; 10(5):1-18. DOI:10.1007/s11306-014-0639-9 · 3.86 Impact Factor
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    • "The factors activating AMPK in mammary glands of obese dams are unclear at present. Diet-induced obesity has been shown to impair AMPK regulation by leptin, insulin, and sympathetic neural efferent’s in other tissues [56], and aspects of AMPK function appear to be restored with weight loss [57], [58]. However, leptin and free fatty acids, which are elevated in obese individuals [59], [60] and tend to be higher in lactating obese mice (unpublished data), have also been shown to activate AMPK by stimulating its phosphorylation [61], [62]. "
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    ABSTRACT: Maternal metabolic and nutrient trafficking adaptations to lactation differ among lean and obese mice fed a high fat (HF) diet. Obesity is thought to impair milk lipid production, in part, by decreasing trafficking of dietary and de novo synthesized lipids to the mammary gland. Here, we report that de novo lipogenesis regulatory mechanisms are disrupted in mammary glands of lactating HF-fed obese (HF-Ob) mice. HF feeding decreased the total levels of acetyl-CoA carboxylase-1 (ACC), and this effect was exacerbated in obese mice. The relative levels of phosphorylated (inactive) ACC, were elevated in the epithelium, and decreased in the adipose stroma, of mammary tissue from HF-Ob mice compared to those of HF-fed lean (HF-Ln) mice. Mammary gland levels of AMP-activated protein kinase (AMPK), which catalyzes formation of inactive ACC, were also selectively elevated in mammary glands of HF-Ob relative to HF-Ln dams or to low fat fed dams. These responses correlated with evidence of increased lipid retention in mammary adipose, and decreased lipid levels in mammary epithelial cells, of HF-Ob dams. Collectively, our data suggests that maternal obesity impairs milk lipid production, in part, by disrupting the balance of de novo lipid synthesis in the epithelial and adipose stromal compartments of mammary tissue through processes that appear to be related to increased mammary gland AMPK activity, ACC inhibition, and decreased fatty acid synthesis.
    PLoS ONE 05/2014; 9(5):e98066. DOI:10.1371/journal.pone.0098066 · 3.23 Impact Factor
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