Diabetes, obesity, and cancer affect upward of 15% of the world's population. Interestingly, all three diseases juxtapose dysregulated intracellular signaling with altered metabolic state. Exactly which genetic factors define stable metabolic set points in vivo remains poorly understood. Here, we show that hedgehog signaling rewires cellular metabolism. We identify a cilium-dependent Smo-Ca(2+)-Ampk axis that triggers rapid Warburg-like metabolic reprogramming within minutes of activation and is required for proper metabolic selectivity and flexibility. We show that Smo modulators can uncouple the Smo-Ampk axis from canonical signaling and identify cyclopamine as one of a new class of "selective partial agonists," capable of concomitant inhibition of canonical and activation of noncanonical hedgehog signaling. Intriguingly, activation of the Smo-Ampk axis in vivo drives robust insulin-independent glucose uptake in muscle and brown adipose tissue. These data identify multiple noncanonical endpoints that are pivotal for rational design of hedgehog modulators and provide a new therapeutic avenue for obesity and diabetes.

Summary Epigenetics is defined as heritable changes to the transcriptome that are independent on changes in the genome. The biochemical principles that govern epigenetic modifications are DNA methylation and posttranslational modifications of histones, amongst which acetylation/deacetylation and methylation/demethylation of lysine residues are the most widely studied. Such epigenetic changes are involved in many physiological and pathological processes. This essay will focus on the biology of histone methylation and demethylation reactions, highlighting how these reactions depend on “metabolic” cofactors like S-Adenosylmethionine, Flavin Adenine Dinucleotide and α-ketoglutarate. Furthermore, we will illustrate that the absence of lysine methyltranferases and demethylases can lead to altered metabolic homeostasis. Altogether, this provides preliminary evidence that lysine methyltranferases and demethylases could act as molecular transducers of metabolic signals to chromatin, and sets the stage for further research into this area to consolidate these enticing initial observations.

SummaryMore than one-half billion people are obese, and despite progress in genetic research, much of the heritability of obesity remains enigmatic. Here, we identify a Trim28-dependent network capable of triggering obesity in a non-Mendelian, “on/off” manner. Trim28+/D9 mutant mice exhibit a bi-modal body-weight distribution, with isogenic animals randomly emerging as either normal or obese and few intermediates. We find that the obese-“on” state is characterized by reduced expression of an imprinted gene network including Nnat, Peg3, Cdkn1c, and Plagl1 and that independent targeting of these alleles recapitulates the stochastic bi-stable disease phenotype. Adipose tissue transcriptome analyses in children indicate that humans too cluster into distinct sub-populations, stratifying according to Trim28 expression, transcriptome organization, and obesity-associated imprinted gene dysregulation. These data provide evidence of discrete polyphenism in mouse and man and thus carry important implications for complex trait genetics, evolution, and medicine.Video Abstract

SummaryTo date, it remains largely unclear to what extent chromatin machinery contributes to the susceptibility and progression of complex diseases. Here, we combine deep epigenome mapping with single-cell transcriptomics to mine for evidence of chromatin dysregulation in type 2 diabetes. We find two chromatin-state signatures that track β cell dysfunction in mice and humans: ectopic activation of bivalent Polycomb-silenced domains and loss of expression at an epigenomically unique class of lineage-defining genes. β cell-specific Polycomb (Eed/PRC2) loss of function in mice triggers diabetes-mimicking transcriptional signatures and highly penetrant, hyperglycemia-independent dedifferentiation, indicating that PRC2 dysregulation contributes to disease. The work provides novel resources for exploring β cell transcriptional regulation and identifies PRC2 as necessary for long-term maintenance of β cell identity. Importantly, the data suggest a two-hit (chromatin and hyperglycemia) model for loss of β cell identity in diabetes.

Obesity and diabetes represent key healthcare challenges of our day, affecting upwards of one billion people worldwide. These individuals are at higher risk for cancer, stroke, blindness, heart and cardiovascular disease, and to date, have no effective long-term treatment options available. Recent and accumulating evidence has implicated the developmental morphogen Hedgehog and its downstream signalling in metabolic control. Generally thought to be quiescent in adults, Hedgehog is associated with several human cancers, and as such, has already emerged as a therapeutic target in oncology. Here, we attempt to give a comprehensive overview of the key signalling events associated with both canonical and non-canonical Hedgehog signalling, and highlight the increasingly complex regulatory modalities that appear to link Hedgehog and control metabolism. We highlight these key findings and discuss their impact for therapeutic development, cancer and metabolic disease.