Burn calories! Fighting against obesity by activating beige fat development

Obesity and overweight are issues of rising global concern. They increase the risk of developing non-communicable diseases such as diabetes, hypertension, heart disease, and stroke. With its increasing prevalence, scientists are working on different ways to decrease obesity and effective ways to lose weight. There are four kinds of adipocytes in mammals. They are white, beige, pink, and brown. White adipose tissue is associated with oxidative stress, inflammation, obesity, and increases the risk of metabolic diseases. However, brown adipose tissue has more mitochondria (powerhouses of the cell) and plays a major role in the generation of heat in response to cold. This property of thermogenesis plays an important role in weight loss, obesity, and the prevention of metabolic diseases. On exposure to cold or exercise, white adipocytes turn into beige adipocytes by the expression of Ucp1 proteins at the level of the mitochondria. This process of change of white adipose tissue to beige adipose tissue (which acts like brown adipose tissue) is known as Browning.

Apolipoprotein E is a part of lipoprotein particles produced by the liver and has a crucial role in lipid metabolism in adipose tissue. It facilitates the transfer of fats into the adipocytes, and metabolism of very low-density lipoproteins. Human apolipoprotein E genes (APOE) are commonly expressed as E2, E3, and E4 isoforms. APOE4 is strongly associated with obesity and other metabolic diseases.

To study the effect of Apolipoprotein E (ApoE) on obesity, National Taiwan University scientists: Chung-Lin Jiang (graduate student), Ying-Fang Chen (graduate student), and led by Professor Fu-Jung Lin conducted an elegant molecular study in ApoE KO mice. ApoE4 in humans and mice are 70% similar in structure, which makes mice a suitable experimental animal model to study the effect of Apolipoprotein and its deficiency in browning of adipose tissue and obesity. The research team demonstrated that serum levels of β-hydroxybutyrate(ketone bodies), browning of the white adipose tissue, and body temperatures are higher in ApoE KO mice than in wild-type mice. They also proved that Ucp1 expression is induced in adipose tissue by the production of β-hydroxybutyrate in ApoE deficient mice. The increased Ucp1 expression can also be blocked by treatment with ketogenesis inhibitors in differentiated adipocytes. Scientists concluded that apolipoprotein E deficiency increases the expression of CD36 gene, and increases the uptake and metabolism of fatty acids, thus enhancing the production of β-hydroxybutyrate in white adipose tissues. The original research article is now published in FASEB Journal.

The researchers observed wild-type mice gained more weight than ApoE KO mice, even after providing the same food and being kept in the same environmental conditions. They also found that the number and size of adipocytes are less in KO mice when compared to wild-type mice. They also observed that thermogenesis, energy expenditure, and browning of adipose tissue are higher in ApoE KO mice compared to wild-type mice. This effect of apolipoprotein E deficiency is increased by treatment with Rosiglitazone (PPARγ agonist). They also noticed a decreased accumulation of lipids, increased number of mitochondria, increased insulin sensitivity, and increased utilization of glucose in adipocytes derived from ApoE KO mice when compared to those derived from wild-type mice. The authors observed an increased expression of brown fat genes in adipose tissue of ApoE KO mice than in wild-type mice. They have also observed that apolipoprotein E deficiency increased the expression of genes responsible for regulating ketogenesis and increased the production of β-hydroxybutyrate in adipose precursor cells. Moreover, ApoE deficiency facilitates the differentiation of beige adipocytes by increasing the production of β-hydroxybutyrate. For example, ApoE deficiency enhances the expression of CD36 gene, and the utilization of fatty acids by adipocytes. They have also noticed that level of triglycerides is lower, and the production of β-hydroxybutyrate is higher in ApoE KO adipocytes than wild-type adipocytess, after the treatment with Rosiglitazone. 

In summary, National Taiwan University researchers successfully analyzed and demonstrated the importance of ApoE on lipid metabolism, uptake of fatty acids, browning of adipocytes, levels of β-hydroxybutyrate, adipose tissue, and weight. The crucial role of ApoE in the browning of adipose tissue, accumulation of fat, will have an important impact on better management of obesity.

The research was funded by Ministry of Science and Technology, Taiwan (MOST), Grant Number: MOST 107-2320-B-002-004-MY3