Increased mitochondrial and lipid metabolism is a conserved effect of Insulin/PI3K pathway downregulation in adipose tissue

Abstract

The Insulin/IGF-1 signalling (IIS) pathway plays an essential role in the regulation of glucose and lipid homeostasis. At the same time, a reduction in the IIS pathway activity can extend lifespan and healthspan in various model organisms. Amongst a number of body organs that sense and respond to insulin/IGF-1, the adipose tissue has a central role in both the metabolic and lifespan effects of IIS at the organismal level. Genetic inactivation of IIS components specifically in the adipose tissue has been shown before to improve metabolic profile and extend lifespan in various model organisms. We sought to identify conserved molecular mechanisms that may underlie the beneficial effects of IIS inhibition in the adipose tissue, specifically at the level of phosphoinositide 3-kinase (PI3K), a key IIS effector molecule. To this end, we inactivated PI3K by genetic means in the fly fat body and by pharmacological inhibition in mammalian adipocytes. Gene expression studies revealed changes to metabolism and upregulation of mitochondrial activity in mouse adipocytes and fly fat bodies with downregulated PI3K, which were confirmed by biochemical assays in mammalian adipocytes. These data suggest that PI3K inactivation has a conserved effect of upregulating mitochondrial metabolism in both fly and mammalian adipose tissue, which likely contributes to the health-and lifespan extending effect of IIS pathway downregulation.

DO‐SRS imaging of diet regulated metabolic activities in Drosophila during aging processes

“…Genetic inactivation of the IIS pathway in Drosophila and C. elegans has been shown to extend their lifespans (Broughton et al, 2005;Clancy et al, 2001;Kenyon et al, 1993;Giannakou et al, 2004;Nässel et al, 2015). The phospho- (Bettedi et al, 2020), and downregulation by genetic modulation of the IIS pathway in invertebrates has been associated with prolonged lifespan (Tatar et al, 2003). Our results also revealed the increased lipid metabolism as a conserved effect of downregulating InR/PI3K pathway, as in ppl-Gal4>UAS-Pten flies.…”

“…Further comparing lipid metabolism in each fly mutant during aging revealed that genetic downregulation of InR/PI3K pathway would maintain the relatively high lipid metabolism in flies ( ppl ‐ Gal4 > UAS ‐ Pten ) with aging (Figure S4c ), but upregulation ( ppl ‐ Gal4 > UAS ‐ InR del ) or inactivation ( ppl ‐ Gal4 > UAS ‐ InR DN ) of the pathway led to significant decreases of lipid metabolism in aged flies (Figure S4b,d ), similarly as in the control (Figure S4a ). A recent study on mouse adipose tissue and fly fat body showed that downregulation of InR/PI3K pathway increased lipid metabolism as a conserved effect (Bettedi et al, 2020 ), and downregulation by genetic modulation of the IIS pathway in invertebrates has been associated with prolonged lifespan (Tatar et al, 2003 ). Our results also revealed the increased lipid metabolism as a conserved effect of downregulating InR/PI3K pathway, as in ppl ‐ Gal4 > UAS ‐ Pten flies.…”

Dominant Role of PI3K p110α over p110β in Insulin and β-Adrenergic Receptor Signalling

“…PI3Ks p110α and p110β have been pursued as therapeutic targets mainly in oncology [ 9 ]. However, inhibition of p110α has recently been shown to increase energy expenditure through potentiation of β-AR signalling and enhancement of mitochondrial activity in adipocytes [ 8 , 10 ]. The potentiating effect of p110α inhibition in β-AR signalling has also been shown in human adipose tissue [ 11 ].…”