Abstract
Animals often develop in environments where conditions such as food, oxygen and temperature fluctuate. The ability to adapt their metabolism to these fluctuations is important for normal development and viability. In most animals, low oxygen (hypoxia) is deleterious. However some animals can alter their physiology to tolerate hypoxia. Here we show that TORC1 modulation in adipose tissue is required for organismal adaptation to hypoxia in Drosophila. We find that hypoxia rapidly suppresses TORC1 signaling in Drosophila larvae via TSC-mediated inhibition of Rheb. We show that this hypoxia-mediated inhibition of TORC1 specifically in the larval fat body is essential for viability. Moreover, we find that these effects of TORC1 inhibition on hypoxia tolerance are mediated through remodeling of fat body lipid storage. These studies identify the larval adipose tissue as a key hypoxia-sensing tissue that coordinates whole-body development and survival to changes in environmental oxygen by modulating TORC1 and lipid metabolism.
Highlights
Animals often develop in environments where conditions such as food, oxygen and temperature fluctuate
We found that the hypoxia-exposed animals had a reduced wandering third instar larval weight (Fig. 1b) and reduced final pupal size (Fig. 1c)
We explored a role for three other potential hypoxic regulators of TORC1: AMPK, which is activated under hypoxia in mammalian cell culture and can suppress TORC1 signalling, in part by phosphorylating and inhibiting TSC228,33,34; Ptp61F, a phosphatase previously shown to regulate TORC1 in Drosophila cultured cells exposed to hypoxia[35]; and nitric oxide, which is induced upon hypoxia in Drosophila and which is required for survival in low oxygen[25,26]
Summary
Animals often develop in environments where conditions such as food, oxygen and temperature fluctuate. We find that hypoxia rapidly suppresses TORC1 signaling in Drosophila larvae via TSC-mediated inhibition of Rheb. We find that these effects of TORC1 inhibition on hypoxia tolerance are mediated through remodeling of fat body lipid storage These studies identify the larval adipose tissue as a key hypoxia-sensing tissue that coordinates whole-body development and survival to changes in environmental oxygen by modulating TORC1 and lipid metabolism. Nutrient activation of TORC1 in specific larval tissues such as the fat body, muscle and prothoracic gland, can influence whole animal development through the control of endocrine signalling via insulin-like peptides and the steroid hormone, ecdysone[9,10,15]. TORC1 regulation of autophagy in the larval fat body is important for organismal homeostasis and survival during periods of nutrient deprivation[16,17]. Developmental hypoxia sensing and signalling has been shown to be mediated through a nitric oxide/cGMP/PKG signalling pathway[25,26]
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