AMPK supports growth in Drosophila by regulating muscle activity and nutrient uptake in the gut

Department of Medicine, Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania, Philadelphia, PA 19104, USA.
Developmental Biology (Impact Factor: 3.55). 08/2010; 344(1):293-303. DOI: 10.1016/j.ydbio.2010.05.010
Source: PubMed


The larval phase of the Drosophila life cycle is characterized by constant food intake, resulting in a two hundred-fold increase in mass over four days. Here we show that the conserved energy sensor AMPK is essential for nutrient intake in Drosophila. Mutants lacking dAMPKalpha are small, with low triglyceride levels, small fat body cells and early pupal lethality. Using mosaic analysis, we find that dAMPKalpha functions as a nonautonomous regulator of cell growth. Nutrient absorption is impaired in dAMPKalpha mutants, and this defect stems not from altered gut epithelial cell polarity but from impaired peristaltic activity. Expression of a wild-type dAMPKalpha transgene or an activated version of the AMPK target myosin regulatory light chain (MRLC) in the dAMPKalpha mutant visceral musculature restores gut function and growth. These data suggest strongly that AMPK regulates visceral smooth muscle function through phosphorylation of MRLC. Furthermore, our data show that in Drosophila, AMPK performs an essential cell-nonautonomous function, serving the needs of the organism by promoting activity of the visceral musculature and, consequently, nutrient intake.

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    • "The AMPK pathway senses energy levels in the cell by responding to intracellular adenosine nucleotide levels to regulate growth and metabolism in Drosophila larvae (Braco et al., 2012; Mihaylova and Shaw, 2012). In Drosophila larvae, blocking AMPK signaling appears to regulate growth by affecting contraction of the visceral muscle, thereby interfering with gut function (Bland et al., 2010). In mammals, AMPK signaling interacts with IIS/TOR by regulating TSC1/2 (Mihaylova and Shaw, 2012). "
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    • "ampkα mutants grown under energy stress have defects in apical/basal epithelial cell polarity in follicle cells within the ovary (Mirouse et al., 2007). In contrast, AMPKα mutants grown on nutrient rich food still show defects in embryonic epithelial polarity (Lee et al., 2007), neuroblast apical polarity (this work), and visceral muscle contraction (Bland et al., 2010). Larval neuroblasts, embryonic ectoderm, and visceral muscle may have a high metabolic rate, require low basal AMPK activity, or use a different mechanism to activate AMPK than epithelial cells. "
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    • "AMPK may participate in this specialized population of cells to regulate AKH signaling, as well as in other potential cells including insulin [42], which is known to participate in the endocrine events that shape behavioral and physiological responses to starvation. During preparation of this manuscript, two independent reports showed similar phenotypes stemming from reduced AMPK function [36], [43]. One report showed a similar sensitivity to starvation conditions as we have, in Drosophila with reduced AMPK function through selective introduction of an RNAi element targeting the alpha subunit. "
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    ABSTRACT: Organisms must utilize multiple mechanisms to maintain energetic homeostasis in the face of limited nutrient availability. One mechanism involves activation of the heterotrimeric AMP-activated protein kinase (AMPK), a cell-autonomous sensor to energetic changes regulated by ATP to AMP ratios. We examined the phenotypic consequences of reduced AMPK function, both through RNAi knockdown of the gamma subunit (AMPKγ) and through expression of a dominant negative alpha (AMPKα) variant in Drosophila melanogaster. Reduced AMPK signaling leads to hypersensitivity to starvation conditions as measured by lifespan and locomotor activity. Locomotor levels in flies with reduced AMPK function were lower during unstressed conditions, but starvation-induced hyperactivity, an adaptive response to encourage foraging, was significantly higher than in wild type. Unexpectedly, total dietary intake was greater in animals with reduced AMPK function yet total triglyceride levels were lower. AMPK mutant animals displayed starvation-like lipid accumulation patterns in metabolically key liver-like cells, oenocytes, even under fed conditions, consistent with a persistent starved state. Measurements of O(2) consumption reveal that metabolic rates are greater in animals with reduced AMPK function. Lastly, rapamycin treatment tempers the starvation sensitivity and lethality associated with reduced AMPK function. Collectively, these results are consistent with models that AMPK shifts energy usage away from expenditures into a conservation mode during nutrient-limited conditions at a cellular level. The highly conserved AMPK subunits throughout the Metazoa, suggest such findings may provide significant insight for pharmaceutical strategies to manipulate AMPK function in humans.
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