The Drosophila HNF4 nuclear receptor promotes glucose-stimulated insulin secretion and mitochondrial function in adults

Abstract

Although mutations in HNF4A were identified as the cause of Maturity Onset Diabetes of the Young 1 (MODY1) two decades ago, the mechanisms by which this nuclear receptor regulates glucose homeostasis remain unclear. Here we report that loss of Drosophila HNF4 recapitulates hallmark symptoms of MODY1, including adult-onset hyperglycemia, glucose intolerance and impaired glucose-stimulated insulin secretion (GSIS). These defects are linked to a role for dHNF4 in promoting mitochondrial function as well as the expression of Hex-C, a homolog of the MODY2 gene Glucokinase. dHNF4 is required in the fat body and insulin-producing cells to maintain glucose homeostasis by supporting a developmental switch toward oxidative phosphorylation and GSIS at the transition to adulthood. These findings establish an animal model for MODY1 and define a developmental reprogramming of metabolism to support the energetic needs of the mature animal.DOI: http://dx.doi.org/10.7554/eLife.11183.001

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.…”

“…Gene expression data related to various studies [1][2][3][4]8,[11][12][13][14][15][16][17][18] were used for gene overlap analysis, as outlined in Fig. 1A.…”

“…1A), overlap of gene sets showing inheritance of cold-induced effects [1] with genes showing differential expression in flies fed with various diets [8,[11][12][13]. We tested HSD, highfat diet (HFD), and high-protein diet (HPD) as well as flies mutants for or ectopically expressing [14][15][16][17][18] transcription factors (TFs) or TF-binding proteins involved in metabolic regulation. As expected, we found that gene sets associated with cold [1] are enriched for metabolic genes [8,[11][12][13][14][15][16][17][18] in general (Fig.…”

Adult functions for the Drosophila DHR78 nuclear receptor

“…Table S1) (Carlson and Hogness, 1985). In contrast, comparisons of our data with published datasets revealed no significant overlaps with genes regulated by the DHR38, DHR96, or dHNF4 nuclear receptors (Sieber and Thummel, 2009; Ruaud et al, 2011; Barry and Thummel, 2016). Taken together, this data suggests that DHR78 plays a major role in regulating genes in the adult midgut, including enzymes that promote nutrient uptake.…”

Microbiota regulate intestinal epithelial gene expression by suppressing the transcription factor Hepatocyte nuclear factor 4 alpha

“…HNF4A has been characterized as a master metabolic regulator for its conserved roles in gluconeogenesis, glucose homeostasis, and fatty acid metabolism (Palanker et al 2009;Frochot et al 2012;Barry and Thummel 2016). Despite its clear importance in metabolic health, relatively little insight into its regulation in a biological context has been reported.…”