Deletion of the Mammalian INDY Homolog Mimics Aspects of Dietary Restriction and Protects against Adiposity and Insulin Resistance in Mice

Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT 06520, USA.
Cell metabolism (Impact Factor: 17.57). 08/2011; 14(2):184-95. DOI: 10.1016/j.cmet.2011.06.009
Source: PubMed


Reduced expression of the Indy (I'm Not Dead, Yet) gene in D. melanogaster and its homolog in C. elegans prolongs life span and in D. melanogaster augments mitochondrial biogenesis in a manner akin to caloric restriction. However, the cellular mechanism by which Indy does this is unknown. Here, we report on the knockout mouse model of the mammalian Indy (mIndy) homolog, SLC13A5. Deletion of mIndy in mice (mINDY(-/-) mice) reduces hepatocellular ATP/ADP ratio, activates hepatic AMPK, induces PGC-1α, inhibits ACC-2, and reduces SREBP-1c levels. This signaling network promotes hepatic mitochondrial biogenesis, lipid oxidation, and energy expenditure and attenuates hepatic de novo lipogenesis. Together, these traits protect mINDY(-/-) mice from the adiposity and insulin resistance that evolve with high-fat feeding and aging. Our studies demonstrate a profound effect of mIndy on mammalian energy metabolism and suggest that mINDY might be a therapeutic target for the treatment of obesity and type 2 diabetes.

Download full-text


Available from: Francois Jornayvaz,
  • Source
    • "In line with this premise, Inoue et al. (2003) showed that lithium stimulation significantly increased SLC13A5-dependent [ 14 C]citrate uptake and incorporation into lipids in HepG2 cells. Most recently, utilizing Slc13a5 knockout mice, Birkenfeld et al. (2011) demonstrated that mice lacking Slc13a5 expression were protected from high-fat diet–induced obesity and insulin resistance; in particular, deletion of Slc13a5 prevents lipid accumulation in the liver. In the current study, we showed that, as a potent inducer of SLC13A5, RIF enhances lipid accumulation in HPH. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The solute carrier family 13 member 5 (SLC13A5) is a sodium-coupled transporter that mediates cellular uptake of citrate, which plays important roles in the synthesis of fatty acids and cholesterol. Recently, the pregnane X receptor (PXR, NR1I2) initially characterized as a xenobiotic sensor, has been functionally linked to the regulation of various physiological processes that are associated with lipid metabolism and energy homeostasis. Here, we show that the SLC13A5 gene is a novel transcriptional target of PXR and altered expression of SLC13A5 affects lipid accumulation in human liver cells. The prototypical PXR activator rifampicin markedly induced the mRNA and protein expression of SLC13A5 in human primary hepatocytes. Utilizing cell-based luciferase reporter assays, electrophoretic mobility shift assays, and chromatin immunoprecipitation assays, we identified and functionally characterized two enhancer modules located upstream of the SLC13A5 gene transcription start site, that are associated with regulation of PXR-mediated SLC13A5 induction. Functional analysis further revealed that rifampicin can enhance lipid accumulation in human primary hepatocytes; and knockdown of SLC13A5 expression alone leads to significant decrease of the lipid content in HepG2 cells. Overall, our results uncover SLC13A5 as a novel target gene of PXR and may contribute to drug-induced steatosis and metabolic disorders in humans. The American Society for Pharmacology and Experimental Therapeutics.
    Molecular pharmacology 01/2015; 87(4). DOI:10.1124/mol.114.097287 · 4.13 Impact Factor
  • Source
    • "AMPK activation promotes mitochondrial biogenesis through the transcriptional regulation of several nuclear genes. Studies in primary muscle cells and mice showed that AMPK directly phosphorylates PGC-1α and induces mitochondrial biogenesis (Birkenfeld et al., 2011; Jager et al., 2007). AMPK also stimulates SIRT1 activity by increasing cellular NAD + levels. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mitochondria are highly dynamic organelles and their proper function is crucial for the maintenance of cellular homeostasis. Mitochondrial biogenesis and mitophagy are two pathways that regulate mitochondrial content and metabolism preserving homeostasis. The tight regulation between these opposing processes is essential for cellular adaptation in response to cellular metabolic state, stress and other intracellular or environmental signals. Interestingly, imbalance between mitochondrial proliferation and degradation process results in progressive development of numerous pathologic conditions. Here we review recent studies that highlight the intricate interplay between mitochondrial biogenesis and mitophagy, mainly focusing on the molecular mechanisms that govern the coordination of these processes and their involvement in age-related pathologies and ageing.
    Experimental gerontology 08/2014; 56. DOI:10.1016/j.exger.2014.01.021 · 3.49 Impact Factor
  • Source
    • "Hepatic lipogenesis contributes significantly to body fat accumulation and metabolic diseases [1]. Previous research has indicated that hepatic lipogenesis plays a part in the development of obesity, and knockdown of hepatic lipogenic pathways can blunt both steatosis and weight gain in nonhuman models [2]. With obesity rates expected to rise to 50% of US adults by 2030, contributing up to 8.5 million additional cases of diabetes, it is imperative that the metabolic disturbances that occur during the onset of obesity are delineated [3]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: High-fat diets (HFD) promote the development of both obesity and fatty liver disease through the up-regulation of hepatic lipogenesis. Insulin resistance, a hallmark of both conditions, causes dysfunctional fuel partitioning and increases in lipogenesis. Recent work has demonstrated that systemic insulin resistance occurs in as little as the first 72 hours of an HFD, suggesting the potential for hepatic disruption with HFD at this time point. The current study sought to determine differences in expression of lipogenic genes between sexes in 3-month-old male and female Long-Evans rats after 72 hours of a 40% HFD or a 17% fat (chow) diet. Owing to the response of estrogen on hepatic signaling, we hypothesized that a sexual dimorphic response would occur in the expression of lipogenic enzymes, inflammatory cytokines, apoptotic, and cell repair and remodeling genes. Both sexes consumed more energy when fed an HFD compared with their low fat-fed controls. However, only the males fed the HFD had a significant increase in body fat. Regardless of sex, HFD caused down-regulation of lipogenic and inflammatory genes. Interestingly, females fed an HFD had up-regulated expression of apoptotic and cell repair-related genes compared with the males. This may suggest that females are more responsive to the acute hepatic injury effects caused by HFDs. In summary, neither male nor female rats displayed disrupted hepatic metabolic pathways after 72 hours of the HFD treatment. In addition, female rats appear to have protection from increases in fat deposition, possibly due to increased caloric expenditure; male rats fed an HFD were less active, as demonstrated by distance traveled in their home cage.
    Nutrition research 01/2014; 34(1):85-93. DOI:10.1016/j.nutres.2013.10.010 · 2.47 Impact Factor
Show more