Sir2 Acts through Hepatocyte Nuclear Factor 4 to maintain insulin Signaling and Metabolic Homeostasis in Drosophila

Abstract

SIRT1 is a member of the sirtuin family of NAD+-dependent deacetylases, which couple cellular metabolism to systemic physiology. Although studies in mouse models have defined a central role for SIRT1 in maintaining metabolic health, the molecular mechanisms remain unclear. Here we show that loss of the Drosophila SIRT1 homolog sir2 leads to the age-progressive onset of hyperglycemia, obesity, glucose intolerance, and insulin resistance. Tissue-specific functional studies show that Sir2 is both necessary and sufficient in the fat body (analogous to the mammalian liver) to maintain glucose homeostasis and peripheral insulin sensitivity. Transcriptional profiling of sir2 mutants by RNA-seq revealed a major overlap with genes regulated by the nuclear receptor Hepatocyte Nuclear Factor 4 (HNF4). Consistent with this, Drosophila HNF4 mutants display diabetic phenotypes similar to those of sir2 mutants, and protein levels for dHNF4 are reduced in sir2 mutant animals. We show that Sir2 exerts these effects by deacetylating and stabilizing dHNF4 through protein interactions. Increasing dHNF4 expression in sir2 mutants is sufficient to rescue their insulin signaling defects, defining this nuclear receptor as an important downstream effector of Sir2 signaling. This study demonstrates that the key metabolic activities of SIRT1 have been conserved through evolution, provides a genetic model for functional studies of phenotypes related to type 2 diabetes, and establishes HNF4 as a critical downstream target by which Sir2 maintains metabolic health.

Transgenerational inheritance of cold temperature response in Drosophila

“…) gene enrichment together is also in agreement with the well‐established relationship between intestinal bacteria and metabolism in diverse species including fly . As TAG levels were found altered in several of the above metabolic studies , are associated with cold tolerance in D. melanogaster , and, notably, show alterations in the offspring of cold‐exposed mice , we identified altered TAG regulation as a potential trait that might be inherited following cold exposure.…”

Hepatocyte Nuclear Factor 4 Alpha Activation Is Essential for Termination of Liver Regeneration in Mice

“…Transcription factors, including HNF4A, HNF1A, PPARGC1A, and Esrra, were inhibited at day 2 post‐PH and continued to be inhibited at day 5 post‐PH. Inhibition of sirtuin 2 (SIRT2) was observed at 5 days post‐PH in HNF4α‐KO mice, consistent with its known role in sharing many of the same target genes as HNF4α, Peroxisome proliferator‐activated receptor gamma coactivator 1‐beta (PPARGC1B) is a known coactivator of PPARGC1A and was inhibited. Nuclear receptor coactivator 2 (NCOA2) and early B‐cell factor 1 (EBF1), known tumor suppressors, were inhibited in HNF4α‐KO mice day 5 post‐PH.…”

Central metabolic-sensing remotely controls nutrient –sensitive endocrine response in Drosophila via Sir2/Sirt1-upd2-IIS axis

“…In this regard, hepatic and adipocyte-specific disruption of Sirt1 results in hyperinsulinemia in mammals (Purushotham et al, 2009;Wang et al, 2011;Gillum et al, 2011), but the mechanisms are poorly understood. Although a role for Sir2/Sirt1 in controlling dILP2 secretion was identified (Palu and Thummel, 2016), the tissue of origin of Sir2/Sirt1-dependent dILP control is still unknown.…”

“…Previous reports from our lab and others have indicated a possible role for Sir2/Sirt1 in distant tissues in regulating insulin production and secretion (Palu and Thummel, 2016;Schenk et al, 2011;Wang et al, 2011;Purushotham et al, 2009;Banerjee et al, 2013). However, the mechanistic details and the physiological understanding of this endocrine control are currently lacking.…”

“…A recent study reported that Sir2/Sirt1 is a negative regulator of dILP2 secretion (Palu and Thummel, 2016). However, whether this is mediated in a tissue-autonomous or -nonautonomous manner was unclear.…”