Inhibition of class I HDACs imprints adipogenesis toward oxidative and brown-like phenotype.

Obesity is characterized by uncontrolled expansion of adipose tissue mass, resulting in adipocyte hypertrophy (increased adipocyte size) and hyperplasia (increased number of adipocytes). The number of adipose cells is directly related to adipocyte differentiation process from stromal vascular cells to mature adipocytes. It is known that epigenetic factors influence adipose differentiation program. However, how specific epigenome modifiers affect white adipocyte differentiation and metabolic phenotype is still matter of research. Here, we provide evidence that class I histone deacetylases (HDACs) are involved both in the differentiation of adipocytes and in determining the metabolic features of these cells. We demonstrate that inhibition of class I HDACs from the very first stage of differentiation amplifies the differentiation process and imprints cells toward a highly oxidative phenotype. These effects are related to the capacity of the inhibitor to modulate H3K27 acetylation on enhancer regions regulating Pparg and Ucp1 genes. These epigenomic modifications result in improved white adipocyte functionality and metabolism and induce browning. Collectively, our results show that modulation of class I HDAC activity regulates the metabolic phenotype of white adipocytes via epigenetic imprinting on a key histone mark.

Ketogenic Diet: A New Light Shining on Old but Gold Biochemistry.

Diets low in carbohydrates and proteins and enriched in fat stimulate the hepatic synthesis of ketone bodies (KB). These molecules are used as alternative fuel for energy production in target tissues. The synthesis and utilization of KB are tightly regulated both at transcriptional and hormonal levels. The nuclear receptor peroxisome proliferator activated receptor α (PPARα), currently recognized as one of the master regulators of ketogenesis, integrates nutritional signals to the activation of transcriptional networks regulating fatty acid ß-oxidation and ketogenesis. New factors, such as circadian rhythms and paracrine signals, are emerging as important aspects of this metabolic regulation. However, KB are currently considered not only as energy substrates but also as signaling molecules. ß-hydroxybutyrate has been identified as class I histone deacetylase inhibitor, thus establishing a connection between products of hepatic lipid metabolism and epigenetics. Ketogenic diets (KD) are currently used to treat different forms of infantile epilepsy, also caused by genetic defects such as Glut1 and Pyruvate Dehydrogenase Deficiency Syndromes. However, several researchers are now focusing on the possibility to use KD in other diseases, such as cancer, neurological and metabolic disorders. Nonetheless, clear-cut evidence of the efficacy of KD in other disorders remains to be provided in order to suggest the adoption of such diets to metabolic-related pathologies.

Epigenome modifiers and metabolic rewiring: New frontiers in therapeutics.

In the last decade numerous publications highlighted the connection between metabolism and epigenetics in different physiological and pathological conditions. The availability of metabolites for cells represents indeed a crucial factor, which is able to condition cell fate and development, differentiation and proliferation partially trough epigenetic control. This tight link provides novel therapeutic possibilities to treat many pathological conditions induced by epigenetic alterations, by manipulating metabolic pathways producing metabolites that work also as epigenetic modifiers. This review will explore specifically the relevance of epigenetics and metabolism in the onset of metabolic disorders and cancer, highlighting potential epigenetic-based pharmacological approaches for the treatment of these disorders trough a rewiring of cellular metabolism. We will also report recent studies on stem cells, demonstrating how epigenetic setting is influenced by metabolism and how these processes affect cell pluripotency and differentiation capacity. These findings suggest a big pharmacological potential, as the modulation of epigenetics and metabolism in stem cells may represent a new tool for regenerative medicine, offering a plethora of novel possibilities for the treatment of severe pathological conditions.

HDAC3 is a molecular brake of the metabolic switch supporting white adipose tissue browning.

White adipose tissue (WAT) can undergo a phenotypic switch, known as browning, in response to environmental stimuli such as cold. Post-translational modifications of histones have been shown to regulate cellular energy metabolism, but their role in white adipose tissue physiology remains incompletely understood. Here we show that histone deacetylase 3 (HDAC3) regulates WAT metabolism and function. Selective ablation of Hdac3 in fat switches the metabolic signature of WAT by activating a futile cycle of de novo fatty acid synthesis and ß-oxidation that potentiates WAT oxidative capacity and ultimately supports browning. Specific ablation of Hdac3 in adipose tissue increases acetylation of enhancers in Pparg and Ucp1 genes, and of putative regulatory regions of the Ppara gene. Our results unveil HDAC3 as a regulator of WAT physiology, which acts as a molecular brake that inhibits fatty acid metabolism and WAT browning.Histone deacetylases, such as HDAC3, have been shown to alter cellular metabolism in various tissues. Here the authors show that HDAC3 regulates WAT metabolism by activating a futile cycle of fatty acid synthesis and oxidation, which supports WAT browning.

Of mice and humans through the looking glass: "reflections" on epigenetics of lipid metabolism.

Over the past decade, epigenetics has emerged as a new layer of regulation of gene expression. Several investigations demonstrated that nutrition and lifestyle regulate lipid metabolism by influencing epigenomic remodeling. Studies on animal models highlighted the role of epigenome modifiers in specific metabolic contexts and established clear links between dysregulation of epigenetic mechanisms and metabolic dysfunction. The relevance of findings in animal models has been translated to humans, as epigenome-wide association studies (EWAS) deeply investigated the relationship between lifestyle and epigenetics in human populations. In this review, we will provide an outlook of recent studies addressing the link between epigenetics and lipid metabolism, by comparing results obtained in animal models and in human subjects.

Weight change in treatment with olanzapine and a psychoeducational approach.

This study assesses the efficacy of an educational and dietary approach in preventing olanzapine-induced weight gain. Eighteen patients affected by schizophrenic disorders were treated with olanzapine and weighed twice-weekly for 24 weeks. A psychoeducational intervention and referral to a nutritionist was introduced from the beginning of olanzapine treatment in 9 patients, and from the 9th week of therapy in 8 patients. Results showed that after 8 weeks of olanzapine treatment, weight gain was contained in the subjects receiving intervention unlike patients without preventive intervention (+0.99+/-3.34 kg vs. +2.96+/-3.08 kg; p<.03). At the end of the trial these patients partly shed their gain (-1.77 kg), presenting a final weight which was not significantly different from baseline (+1.19 kg). Subjects receiving the psychoeducational approach from the beginning were significantly heavier than at baseline (+3.4 kg). Poor dietary compliance correlated significantly with an increase in body weight, while higher mean dosages of olanzapine correlated with better weight-gain control.