New evidence from investigators at the University of Tokyo and Tohoku University in Japan has revealed a molecular mechanism that controls how lifestyle choices and the external environment affect gene expression. This mechanism includes potential targets for next-generation drug discovery efforts to treat metabolic diseases including diabetes and obesity.
The Japanese researchers tracked how the epigenome changes after long-term exposure to cold temperatures, and how those changes cause energy-storing white fat cells to become heat-producing brown-like, or “beige,” fat cells. Findings from the new study were published today in Nature Communications through an article entitled “Histone demethylase JMJD1A coordinates acute and chronic adaptation to cold stress via thermogenic phospho-switch.”
“We believe that this is the first time that anyone has collected data to prove that there are two steps between the environmental stimuli and epigenetic changes,” explained Juro Sakai, M.D., Ph.D., an expert in the epigenetics of metabolism and professor at the University of Tokyo and Tohoku University.
Shivering creates body heat short-term by warming up the muscles, but thermogenesis is the chemical process by which brown fat cells can use lipids (fat) to create heat to keep the body warm long-term. Brown fat is regarded as healthier and is not associated with the metabolic diseases linked to excess white fat. Scientists have long suspected that there may be a stepwise process inside the cell to manage environmental influences on the epigenome, but no specific molecular mechanisms had been identified previously.
“Understanding how the environment influences metabolism is scientifically, pharmacologically, and medically interesting,” Dr. Sakai noted.
Researchers have shown previously that when organisms are cold for a long time, the sympathetic nervous system responds by releasing adrenaline. If cold temperatures persist, those adrenaline signals eventually reach white fat cells. In the current study, the research team set out to uncover the epigenetic control pathway that the cell initiates to make the necessary metabolic switch.
The investigators showed the switch “occurs through a two-step process that requires both β-adrenergic-dependent phosphorylation of S265 and demethylation of H3K9me2 by JMJD1A. The histone demethylation-independent acute Ucp1 induction in BAT and demethylation-dependent chronic Ucp1 expression in beige scWAT provides complementary molecular mechanisms to ensure an ordered transition between acute and chronic adaptation to cold stress.”
The authors continued stating that “JMJD1A mediates two major signaling pathways, namely, β-adrenergic receptor and peroxisome proliferator-activated receptor-γ (PPARγ) activation, via PRDM16-PPARγ-P-JMJD1A complex for beige adipogenesis.”
In short, the epigenetic changes transform white fat cells into beige fat cells, which perform thermogenesis like brown fat cells. More beige fat cells and fewer white fat cells could reduce the symptoms or negative health outcomes of metabolic diseases like diabetes, obesity. Although transforming white fat cells into beige fat cells and increasing thermogenesis is naturally a stress response to chronic cold exposure involving adrenaline, researchers report that the same white-to-beige fat cell transition can be caused without adrenaline or cold stress.
“Our next experiments will look more closely at epigenetic modifications within the thermogenesis signaling pathway so that we may manipulate it,” stated Dr. Sakai.
Current drugs for metabolic diseases rely on hormones that are systemic throughout the entire body or drugs that target entire proteins. Dr. Sakai and his team imagine a future where metabolic disease can be treated by targeting single amino acids.
The JMJD1A protein is involved in a wide variety of other processes, including cancer, infertility, stem cell renewal, and sex determination of an embryo. However, Dr. Sakai's research team has discovered sites within the protein sequence that are extremely specific for controlling different activities of the protein. Manipulating those specific amino acids may provide precision drug targets.