Re-patterning of Skeletal Muscle Energy Metabolism by Fat Storage-inducing Transmembrane Protein 2

Miranda, Diego A.; Koves, Timothy R.; Gross, David A.; Chadt, Alexandra; Al-Hasani, Hadi; Cline, Gary W.; Schwartz, Gary J.; Muoio, Deborah M.; Silver, David L.

doi:10.1074/jbc.m111.297127

Cited by 31 publications

(27 citation statements)

References 49 publications

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“…No significant differences in hydroxylated odd-chain acyl carnitine species ratio C5-OH/C3-OH were detected. Collectively, these data indicate a decline in catabolism of BCAAs and likely a reduced pool of available amino acids to the muscle in the OVX condition (38).…”

Section: Resultsmentioning

confidence: 80%

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Ectopic lipid deposition and the metabolic profile of skeletal muscle in ovariectomized mice

Jackson

Wohlers

Lovering

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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Disruptions of ovarian function in women are associated with increased risk of metabolic disease due to dysregulation of peripheral glucose homeostasis in skeletal muscle. Our previous evidence suggests that alterations in skeletal muscle lipid metabolism coupled with altered mitochondrial function may also develop. The objective of this study was to use an integrative metabolic approach to identify potential areas of dysfunction that develop in skeletal muscle from ovariectomized (OVX) female mice compared with age-matched ovary-intact adult female mice (sham). The OVX mice exhibited significant increases in body weight, visceral, and inguinal fat mass compared with sham mice. OVX mice also had significant increases in skeletal muscle intramyocellular lipids (IMCL) compared with the sham animals, which corresponded to significant increases in the protein content of the fatty acid transporters CD36/FAT and FABPpm. A targeted metabolic profiling approach identified significantly lower levels of specific acyl carnitine species and various amino acids in skeletal muscle from OVX mice compared with the sham animals, suggesting a potential dysfunction in lipid and amino acid metabolism, respectively. Basal and maximal mitochondrial oxygen consumption rates were significantly impaired in skeletal muscle fibers from OVX mice compared with sham animals. Collectively, these data indicate that loss of ovarian function results in increased IMCL storage that is coupled with alterations in mitochondrial function and changes in the skeletal muscle metabolic profile.

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Section: Resultsmentioning

confidence: 80%

“…Odd-chain acyl-carnitine species propionylcarnitine (C3), isovalerylcarnitine (C5), and tiglyl carnitine (C5:1) are products of BCAA catabolism (32,38). Because of the observed decline in skeletal muscle amino acids in OVX mice, we measured C3, C5, and C5:1 species in sham and OVX mice.…”

Section: Resultsmentioning

confidence: 99%

Ectopic lipid deposition and the metabolic profile of skeletal muscle in ovariectomized mice

Jackson

Wohlers

Lovering

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Enterocytes-Because FIT2 has been implicated in LD formation (3,17), we hypothesized that iF2KO mice would have reduced de novo LD formation in enterocytes during an acute fat challenge, a condition that normally involves massive de novo LD formation (28,29). To test this idea, we gavaged fasted mice with a bolus of olive oil before histological analysis.…”

Section: Fit2 Deletion Results In the Absence Of Cytosolic Ld Formatimentioning

confidence: 99%

“…and Death-A purported function of FIT2 is to regulate the formation of LDs in various cell and tissue types (3,17). We previously deleted FIT2 in an adipose tissue knock-out mouse model, leading to defects in LD storage of fat in white adipose tissue (WAT), infiltration of WAT with inflammatory macrophages, death of adipocytes, and metabolic dysfunction typical of lipodystrophies, which was significantly exacerbated by high fat feeding (11).…”

Section: Postnatal Deletion Of Fit2 Leads To Progressive Weight Lossmentioning

confidence: 99%

Postnatal Deletion of Fat Storage-inducing Transmembrane Protein 2 (FIT2/FITM2) Causes Lethal Enteropathy

Goh

Tan

et al. 2015

Journal of Biological Chemistry

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“…Conversely, knockdown of FIT2 in cultured adipocytes or zebrafish significantly decreases TAG storage in LDs. Recent studies show that overexpression of FIT2 in mouse skeletal muscle significantly increases storage of TAG in intramyocellular LDs (30). Interestingly, these mice had increased energy expenditure despite decreased ␤-oxidation of fatty acids in muscle; instead, oxidation of branched-chain amino acids was increased.…”

Section: Er Proteins Are Required For Ld Formation and Expansionmentioning

confidence: 98%

Packaging of Fat: An Evolving Model of Lipid Droplet Assembly and Expansion

Brasaemle

Wolins

2012

Journal of Biological Chemistry

210

166

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Lipid droplets (LDs) are organelles found in most types of cells in the tissues of vertebrates, invertebrates, and plants, as well as in bacteria and yeast. They differ from other organelles in binding a unique complement of proteins and lacking an aqueous core but share aspects of protein trafficking with secretory membrane compartments. In this minireview, we focus on recent evidence supporting an endoplasmic reticulum origin for LD formation and discuss recent findings regarding LD maturation and fusion.Eukaryotic cells produce and traffic membranes that maintain intracellular compartments that facilitate regulation of metabolism by controlling the subcellular localization of metabolites, the concentrations of enzymes and substrates to optimize enzyme reactions, and the isolation of toxic metabolites. Fatty acids supply a major source of energy for organisms but also can be toxic. Cells escape cytotoxicity by esterifying fatty acids into neutral lipids and packaging them into lipid droplets (LDs) 3 coated with phospholipids and proteins. When cells are exposed to excess fatty acids, protein-coated LDs replete with neutral lipids bud from membranes of the endoplasmic reticulum (ER). When levels of exogenous fatty acids wane, the surface proteins of nascent LDs are exchanged for other proteins that serve various functions on mature LDs. Recent studies have established LDs as a distinct organelle.The protein components of LDs have been increasingly studied over the past decade. In chordates and flies, members of the perilipin family of proteins are among the most abundant proteins coating LDs (1, 2). Perilipins interact with both lipid and cytosolic proteins, forming an amphipathic interface between stored lipids and the cytosol. LDs in the cells of various vertebrate tissues are coated with two to four types of perilipin; each unique combination of perilipins imparts tissue-specific management of lipid metabolism. The expression of perilipin 1 is limited to adipocytes of white and brown adipose tissue and steroidogenic cells of the adrenal cortex, testes, and ovaries; moreover, subcellular localization of perilipin 1 is essentially restricted to LDs. Perilipin 2 (formerly adipophilin/ADRP (adipose differentiation-related protein)) and perilipin 3 (formerly TIP47 (tail-interacting protein of 47 kDa)) are ubiquitously expressed and hence contribute to the protein coat of LDs in the majority of cells. Perilipin 2 localizes primarily to LDs. Perilipin 3 is stable in the cytoplasm of cells but rapidly associates with nascent LDs when cells are incubated with fatty acids to promote triacylglycerol (TAG) synthesis and storage. Perilipin 4 (formerly S3-12) is expressed primarily in adipocytes of white adipose tissue and localizes to buds of nascent LDs along the ER. Perilipin 5 (formerly MLDP (myocardial lipid droplet protein)/OXPAT (oxidative protein of the PAT family)/LSDP5 (lipid storage droplet protein 5)) is expressed in oxidative tissues, including cardiac and skeletal muscle, and in brown adipocytes. In addition...

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Re-patterning of Skeletal Muscle Energy Metabolism by Fat Storage-inducing Transmembrane Protein 2

Cited by 31 publications

References 49 publications

Ectopic lipid deposition and the metabolic profile of skeletal muscle in ovariectomized mice

Ectopic lipid deposition and the metabolic profile of skeletal muscle in ovariectomized mice

Postnatal Deletion of Fat Storage-inducing Transmembrane Protein 2 (FIT2/FITM2) Causes Lethal Enteropathy

Packaging of Fat: An Evolving Model of Lipid Droplet Assembly and Expansion

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