High Fat Diet (HFD)-induced obesity is a major contributor to diabetes and cardiovascular disease, but the underlying genetic mechanisms are poorly understood. Here, we use Drosophila to test the hypothesis that HFD-induced obesity and associated cardiac complications have early evolutionary origins involving nutrient-sensing signal transduction pathways. We find that HFD-fed flies exhibit increased triglyceride (TG) fat and alterations in insulin/glucose homeostasis, similar to mammalian responses. A HFD also causes cardiac lipid accumulation, reduced cardiac contractility, conduction blocks and severe structural pathologies, reminiscent of diabetic cardiomyopathies. Remarkably, these metabolic and cardiotoxic phenotypes elicited by HFD are blocked by inhibiting insulin-TOR signaling. Remarkably, reducing insulin-TOR activity by TSC1-2, 4EBP, FOXO) or increasing lipase expression in the myocardium suffices to efficiently alleviate cardiac fat accumulation and dysfunction induced by HFD. We conclude that deregulation of insulin-TOR signaling due to a HFD is responsible for mediating the detrimental effects on metabolism and heart function.

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Changes of somatic stem cell (SSC) functionality has been proposed to contribute to tissue and organismal aging. Because the effects of diet and aging on SSC function can impact organ senescence and longevity, the need to determine the differences between young and old SSC in vivo and elucidating general principles of how SSC respond to diet and aging signals are critically important for many aspects of aging and regenerative biology. However, we have a limited understanding of how SSCs change with age and under different diet conditions as well as how modifying aged SSCs affects organ function. Given the important contributions of the intestine to metabolism, growth, and immunity, we used Drosophila intestinal stem cells (ISCs) as a model system to understand these questions. We show that there is an age‐dependent increase in ISC numbers. Furthermore, using a novel High Fat Diet‐induced obesity model, we also see a similar increase in ISC numbers. Both of these age and High Fat Diet‐induced ISC phenotypes can be prevented by decreasing the insulin‐nutrient sensing Target of Rapamycin (TOR) signaling pathways. Thus, these results show that reduction of insulin‐metabolic pathways provides protection against age‐ and high fat diet‐dependent changes in the ISCs and intestine. Future work will look at how other dietary conditions like Dietary Restriction can also modify the ISC aging phenotypes. These results are highly relevant to metabolic diseases like obesity and diabetes as well as colorectal cancer. In many species, reduction of insulin‐nutrient sensing pathways promotes longevity and these results suggest longevity may be linked to stem cell aging via alterations of these pathways.

In humans, inactivating mutations in MLL4, which encodes a histone H3-lysine 4-methyltransferase, lead to Kabuki syndrome (KS). While dwarfism is a cardinal feature of KS, the underlying etiology remains unclear. Here we report that Mll4 regulates the development of growth hormone-releasing hormone (GHRH)-producing neurons in the mouse hypothalamus. Our two Mll4 mutant mouse models exhibit dwarfism phenotype and impairment of the developmental programs for GHRH-neurons. Our ChIP-seq analysis reveals that, in the developing mouse hypothalamus, Mll4 interacts with the transcription factor Nrf1 to trigger the expression of GHRH-neuronal genes. Interestingly, the deficiency of Mll4 results in a marked reduction of histone marks of active transcription, while treatment with the histone deacetylase inhibitor AR-42 rescues the histone mark signature and restores GHRH-neuronal production in Mll4 mutant mice. Our results suggest that the developmental dysregulation of Mll4-directed epigenetic control of transcription plays a role in the development of GHRHneurons and dwarfism phenotype in mice.