Sakai Laboratory
The environment acts on fat cells

The expression “lifestyle-related disease” will be familiar to most Japanese readers. So how are diseases caused by lifestyles? Do environmental factors such as nutrition and/or other common daily factors rewrite genetic information? We had chance to visit professor Sakai's Lab where has been conducting experiments to come up a new treatment methods to prevent lifestyle-related disease.  

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  Many students from other universities, both in Japan and overseas, join professor Sakai's Lab after learning about Professor Sakai's research

• Metabolic syndrome can cause high blood pressure, diabetes, and hyperlipidemia. For many diseases genetic factors play an important role, but Professor Juro Sakai explains, "Lifestyle-related diseases such as metabolic syndrome are not caused by genetic factors alone. Environmental factors are believed to be even more influential than genetics. "Lifestyle-related diseases are induced by intricately interrelated factors such as environmental stimuli and nutrition. Temporary changes in metabolic functions due to environmental or other factors are retained long-term, recorded as “cell memories.”

  These information produce peoples’ so-called “constitutions,” such as being prone to strokes or heart attacks, and can result in lifestyle-related diseases. It is clear that changed metabolic functions are recorded somewhere in cells, however, the underlyingmechanism by which these changes were recorded remains unclear. Professor Sakai explains, “Cell memory is referred to as ‘metabolic memory’ or the ‘legacy effect’. What we have rapidly been discovering over the past ten years indicating that it is not the result of congenital genetics, but of an acquired chemical modulation, in the form of methylation, of some part of the genome (genetic information). This constitutes the epigenome, which controls the manifestation of genetics.”

For example, monozygotic twins have the same blood types and DNA testing results when born, but as they grow up, they are affected by different external stimuli and conditions. Differences appear in their constitutions, such as one becoming disease-prone, while the other seldom falls ill. These changes are considered to be caused by epigenomes. Conversely, research is also underway on using the metabolic memory recorded in cells in a positive manner, to control diabetes and also to prevent future concomitant diseases.

One cause of metabolic syndrome is obesity. Obesity standards based on BMI^* vary from country to country. In Japan a person with a BMI of 25 or more is considered obese, with twice the likelihood of lifestyle-related diseases such as hyperlipemia, diabetes, and high blood pressure as a non-obese person. Considering the fact that the obesity standard in the U.S. is a BMI of 30 or more, Professor Sakai says “One could conclude that Japanese constitutions are vulnerable to obesity.” The keys to obesity are fat cells. “Fat cells have a bad image, but they are actually important cells, storing the energy needed for vital activity, secreting hormones, and more,” explains Professor Sakai. Then why does fat have a negative image? “White fat cells store energy, but if too much fat is stored they become bloated and start having negative effects, producing obesity.” The main negative impact comes from white fat cells stored around internal organs. These cells cause lifestyle-related diseases. “There are also fatcells that help you lose weight,” says Professor Sakai. “There are two different types of fat cells. The first type, brown fat cells, generate heat and burn fat.” Brown fat cells are closely involved in the activity of catecholamines such as adrenaline and noradrenaline. Catecholamine, also known as the “fight-or-flight hormone,” raises the heart rate and blood pressure in order to make it possible to respond to attacks and emergency situations rapidly and with a high level of focus. They also promote the generation of heat by brown fat cells in order to maintain vital functions in cold environments. This mechanism, it appears, promotes weight loss.

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• White fat cells (left) which store fat, and brown fat cells (right) which burn fat

According to Professor Sakai, fat cells, either white or brown, are differentiated preadipocytes. “The genomic base sequences of both preadipocytes and fat cells are identical, but the genetic fat storage behavior of preadipocytes is inhibited, while the genetic fat storage behavior of fat cells is active. The genetic activity of the cells differs because the genomic information is rewritten after birth -- that is, it is related to the epigenome.” The epigenomic mechanism of preadipocytes was unknown until recently, but a research group including Professor Sakai and Assistant Professor Matsumura analyzed the epigenomes of preadipocytes and discovered the mechanism which prevents preadipocytes from becoming fat cells. Their findings were published in the academic journal Molecular Cell, and featured on its front cover.

* BMI (Body Mass Index): Figure used internationally as an indicator of obesity level. It is defined as the body mass (kg) divided by the square of the body height (m). The same calculation method is used worldwide, but as it mentioned before, obesity standards vary by country. Visceral fat storage is not necessarily correlated with BMI, but BMI is used in specific health check-ups and specific counselling guidance to determine who may be at risk for metabolic syndrome.

“The actual base sequence that conveys genomic information does not change, even when cells divide or turn into other cells. However, the mechanism by which the genomic information of preadipocytes and fat cells controls the activity of the cells differs. Part of the information in the base sequence is rewritten as a result of methylation, which determines if the cell will remain a preadipocyte or turn into a fat cell,” says Professor Sakai. In many preadipocytes the research group found serial chromatin structures (protein structures with DNA wrapped around them) of H3K4me3, which activates fat cells, and H3K9me3, which suppresses them. They ascertained that this structure served as a switch in which preadipocytes differentiated into fat cells. “It appears the H3K9me3 epigenome in preadipocytes suppresses the activity of a limited set of genes, controlling the timing of differentiating the preadipocyte into a fat cell. If the H3K9me3 is eliminated from the preadipocyte the preadipocyte will differentiate into a fat cell, and begin storing fat,” explains Professor Sakai. What external factors produce the preadipocyte’s switch? What controls the switch? How are white and brown fat cells produced? Metabolism presents an unending list of research topics. “Right now we’re doing research into how fat cells turn into white or brown fat cells.” Sakai Lab is attempting to unravel the mechanisms that cause obesity, which is intricately linked to lifestyle-related diseases, in order to develop methods for preventing obesity caused by nutritional and environmental factors, and develop new drug concepts. Japan, and the rest of the world, waits in anticipation for their research results.

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• The obese mouse shown at right lacks the JMJD1A protein that is required for maintaining body temperature by generating heat in cold environment. Mice expend a great deal of energy when placed in 4°C incubator, but this mouse can expend little energy thus exhibit lower temperature. These findings have been published in Nature Communications.

There are two types of fat cells. White fat cells store triglycerides and become enlarged. Brown fat cells can burn fat and turn it into heat, so despite being “fat cells” they help reduce fat levels.

“Molecular Cell” is an academic journal with a high impact factor in the field of molecular biology. The results of Professor Sakai’s team’s research were depicted with an "Alice in Wonderland" motif on the cover of the November 19, 2015 (Vol. 20) issue.

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• Professor Sakai (right) and Research Associate Matsumura (left)

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• Professor Sakai spent his postdoctoral research fellow at the University of Texas under the supervision of professors Goldstein and Brown, who won the Nobel Prize in Physiology or Medicine in 1985 for their discoveries of low density lipoprotein (LDL) receptor and its genetic mutation causes familial hypercholetestrolemia, a research related to the regulation of cholesterol homeostasis. “The research was wonderful, perfect, and truly artistic. I was moved,” says Professor Sakai in a soft voice, with a smile on his face. When asked about Professor Sakai’s usual attitude, Sakai Lab researchers responded, “He never takes shortcuts to increase efficiency. He’s detailed, precise, persistent, and thorough. His attitude towards research is moving.” Professor Sakai himself laughs, “I’ve never approached research from the perspective of efficiency, so I don’t really know…” As a young man Professor Sakai was moved by his former teachers’ research, and he now leads other researchers who feel the same way about him, striving to shed light on major issues of 21st century biomedicine.