Article

Adipose-Specific Knockout of raptor Results in Lean Mice with Enhanced Mitochondrial Respiration

Biozentrum, University of Basel, Basel, CH-4056, Switzerland.
Cell metabolism (Impact Factor: 16.75). 12/2008; 8(5):399-410. DOI: 10.1016/j.cmet.2008.09.003
Source: PubMed

ABSTRACT raptor is a specific and essential component of mammalian TOR complex 1 (mTORC1), a key regulator of cell growth and metabolism. To investigate a role of adipose mTORC1 in regulation of adipose and whole-body metabolism, we generated mice with an adipose-specific knockout of raptor (raptor(ad-/-)). Compared to control littermates, raptor(ad-/-) mice had substantially less adipose tissue, were protected against diet-induced obesity and hypercholesterolemia, and exhibited improved insulin sensitivity. Leanness was in spite of reduced physical activity and unaffected caloric intake, lipolysis, and absorption of lipids from the food. White adipose tissue of raptor(ad-/-) mice displayed enhanced expression of genes encoding mitochondrial uncoupling proteins characteristic of brown fat. Leanness of the raptor(ad-/-) mice was attributed to elevated energy expenditure due to mitochondrial uncoupling. These results suggest that adipose mTORC1 is a regulator of adipose metabolism and, thereby, controls whole-body energy homeostasis.

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    • "However, similar to acute rapamycin treatment, abrogation of mTORC1 activity by raptor deletion increases p-Akt in muscle cells and skeletal muscle [22,38]. Moreover, deletion of raptor in adipose tissue protects mice from high fat diet induced weight gain and improves their glucose tolerance [41]. This indicates that inhibited mTORC1 signaling by AZD8055 likely does not account for the metabolic effects observed by AZD8055. "
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    ABSTRACT: The effect of acute inhibition of both mTORC1 and mTORC2 on metabolism is unknown. A single injection of the mTOR kinase inhibitor, AZD8055, induced a transient, yet marked increase in fat oxidation and insulin resistance in mice, whereas the mTORC1 inhibitor rapamycin had no effect. AZD8055, but not rapamycin reduced insulin-stimulated glucose uptake into incubated muscles, despite normal GLUT4 translocation in muscle cells. AZD8055 inhibited glycolysis in MEF cells. Abrogation of mTORC2 activity by SIN1 deletion impaired glycolysis and AZD8055 had no effect in SIN1 KO MEFs. Re-expression of wildtype SIN1 rescued glycolysis. Glucose intolerance following AZD8055 administration was absent in mice lacking the mTORC2 subunit Rictor in muscle, and in vivo glucose uptake into Rictor-deficient muscle was reduced despite normal Akt activity. Taken together, acute mTOR inhibition is detrimental to glucose homeostasis in part by blocking muscle mTORC2, indicating its importance in muscle metabolism in vivo.
    09/2014; DOI:10.1016/j.molmet.2014.06.004
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    • "Global deletion of mTOR or Raptor in the mouse leads to early postimplantation lethality (Gangloff et al., 2004; Guertin et al., 2006; Murakami et al., 2004). Subsequent tissue-specific knockout studies have identified crucial roles for mTORC1 in several tissues, but its function in skeletal development has not been examined genetically (Bentzinger et al., 2008; Polak et al., 2008; Yilmaz et al., 2012). Here, through deletion of either mTOR or Raptor, we demonstrate that mTORC1 signaling is required for optimal protein production in chondrocytes, thus controlling cell size, the amount of cartilage matrix and, ultimately, skeletal size. "
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    ABSTRACT: Much of the mammalian skeleton is derived from a cartilage template that undergoes rapid growth during embryogenesis, but the molecular mechanism of growth regulation is not well understood. Signaling by mammalian target of rapamycin complex 1 (mTORC1) is an evolutionarily conserved mechanism that controls cellular growth. Here we report that mTORC1 signaling is activated during limb cartilage development in the mouse embryo. Disruption of mTORC1 signaling through deletion of either mTOR or the associated protein Raptor greatly diminishes embryonic skeletal growth associated with severe delays in chondrocyte hypertrophy and bone formation. The growth reduction of cartilage is not due to changes in chondrocyte proliferation or survival, but is caused by a reduction in cell size and in the amount of cartilage matrix. Metabolic labeling reveals a notable deficit in the rate of protein synthesis in Raptor-deficient chondrocytes. Thus, mTORC1 signaling controls limb skeletal growth through stimulation of protein synthesis in chondrocytes.
    Development 06/2014; 141(14). DOI:10.1242/dev.108811 · 6.27 Impact Factor
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    • "Rapamycin treatment [10] or deletion of the TORC1 component Raptor [11], were associated with mitochondrial perturbations in mouse muscle; and in Jurkat T cells repression of mTORC1 was reported to decrease mitochondrial respiration [12]. On the other hand, deletion of TOR, or its target Sch9, has been shown to increase mitochondrial activity in yeasts [13], and mice lacking Raptor in adipose tissue display a higher rate of mitochondrial respiration than controls [14]. Negative regulation of mitochondrial biogenesis by TOR is also supported by work in flies, where dietary restriction elevates the level of the translation repressor d4E-BP (the eukaryotic initiation factor 4E-binding protein), a downstream target of TOR, thereby stimulating transcription in the nucleus of genes that encode mitochondrial components. "
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    ABSTRACT: Amino acids are essential for cell growth and proliferation for they can serve as precursors of protein synthesis, be remodelled for nucleotide and fat biosynthesis, or be burnt as fuel. Mitochondria are energy producing organelles that additionally play a central role in amino acid homeostasis. One might expect mitochondrial metabolism to be geared towards the production and preservation of amino acids when cells are deprived of an exogenous supply. On the contrary, we find that human cells respond to amino acid starvation by upregulating the amino acid-consuming processes of respiration, protein synthesis, and amino acid catabolism in the mitochondria. The increased utilization of these nutrients in the organelle is not driven primarily by energy demand, as it occurs when glucose is plentiful. Instead it is proposed that the changes in the mitochondrial metabolism complement the repression of cytosolic protein synthesis to restrict cell growth and proliferation when amino acids are limiting. Therefore, stimulating mitochondrial function might offer a means of inhibiting nutrient-demanding anabolism that drives cellular proliferation.
    PLoS ONE 04/2014; 9(4):e93597. DOI:10.1371/journal.pone.0093597 · 3.23 Impact Factor
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