Researchers identify epigenetic switch which generates calorie-burning brown fat.


All mammals, including humans, have two types of fat with completely opposite functions.  These are white fat, which stores energy and is linked with diabetes and obesity; and brown fat, which produces heat by burning energy and is associated with leanness.  Many obesity researchers hope to harness the energy-burning capacity of brown fat to help patients lose weight, with just two ounces of this fat type burning up to 200 calories a day when the temperature drops.  However, drugs that activate existing brown fat have proven ineffective in early trials because most people who are obese lack a significant amount of active brown fat. Early drugs also had dangerous cardiovascular side effects, which are of particular concern in obese patients.

Now, a study from researchers at UC San Francisco and University of Kyoto have identified a molecular switch capable of converting unhealthy white fat into healthy, energy-burning brown fat in mice. The team state that drugs which flip this switch rapidly reduced obesity and diabetes risk factors in mice fed a high fat diet.  The opensource study is published in the journal Cell Metabolism.

Earlier studies from the group showed for the first time that brown fat in adult humans consists primarily of so-called ‘beige fat,’ which can transform from white to brown in cold conditions. The discovery immediately suggested a new approach for treating obesity, enhancing people’s baseline stores of energy-burning brown fat, known as the browning of white fat.  Therefore, the natural progression was for the current study to search for differences in how white and brown fat cells respond to the cold using a technique called phosphoproteomics.

The current study identified a protein called Casein Kinase 2 (CK2), which appears to be responsible for preventing white fat from burning energy for heat in cold conditions. Data findings show that when the activity of this molecule is inhibited genetically or pharmacologically, white fat cells lit up their cellular furnaces, becoming calorie burners like their brown and beige counterparts.  Results show that this one protein turned out to be the switch that regulates whether fat cells burn energy or not.

The researchers tested two anti-CK2 molecules for their ability to stimulate the production of new brown fat in mice.  The lab explain that a new small-molecule CK2-blocker called silmitasertib (CX-4945), which is already in clinical trials as a cancer therapeutic; and a more precise next-generation antisense oligonucleotide (ASO) drug developed in collaboration with Isis Pharmaceuticals, which eliminates CK2 by blocking the RNA instructions cells use to produce it.

Results show that both drugs succeeded in turning significant amounts of white fat brown and significantly increasing the amount of energy mice burned when researchers turned down the temperature in their living quarters. The group state that the drugs also significantly reduced the negative effects of a high-fat diet in mice, including reducing weight gain and, to the researchers’ surprise, significantly lowering blood glucose levels and improving responsiveness to insulin.  Results show that CK2 activity is also heightened in obese mice, suggesting a link between obesity and the loss of brown fat.

The current study also showed that CK2 inhibition and cool conditions complement each other to dramatically reduce obesity in mice. The group note that normally, mice fed a high fat diet for 45 days quickly balloon to nearly 160 percent of their starting weight. Data findings show that treating mice with CK2-ASO or housing them at 17 degrees C (62.6 degrees F) each prevented more than 25 percent of this weight gain; in combination the two treatments reduced weight gain by fully 40 percent.

The team surmise that their findings show drugs capable of targeting similar molecular pathways in human fat cells could one day become major tools for fighting the growing worldwide epidemics of obesity and type 2 diabetes.  For the future, the researchers are now examining whether CK2-inhibitors can effectively reduce obesity as well as prevent it, and whether they can be used alongside next-generation drugs that mimic the effects of cold to trigger brown fat to burn energy in humans.

Source: UC San Francisco

 

Catecholamines promote lipolysis both in brown and white adipocytes, whereas the same stimuli preferentially activate thermogenesis in brown adipocytes. Molecular mechanisms for the adipose-selective activation of thermogenesis remain poorly understood. Here, we employed quantitative phosphoproteomics to map global and temporal phosphorylation profiles in brown, beige, and white adipocytes under β3-adrenenoceptor activation and identified kinases responsible for the adipose-selective phosphorylation profiles. We found that casein kinase2 (CK2) activity is preferentially higher in white adipocytes than brown/beige adipocytes. Genetic or pharmacological blockade of CK2 in white adipocytes activates the thermogenic program in response to cAMP stimuli. Such activation is largely through reduced CK2-mediated phosphorylation of class I HDACs. Notably, inhibition of CK2 promotes beige adipocyte biogenesis and leads to an increase in whole-body energy expenditure and ameliorates diet-induced obesity and insulin resistance. These results indicate that CK2 is a plausible target to rewire the β3-adrenenoceptor signaling cascade that promotes thermogenesis in adipocytes.  Phosphoproteomics Identifies CK2 as a Negative Regulator of Beige Adipocyte Thermogenesis and Energy Expenditure.  Kajimura et al 2015.

Catecholamines promote lipolysis both in brown and white adipocytes, whereas the same stimuli preferentially activate thermogenesis in brown adipocytes. Molecular mechanisms for the adipose-selective activation of thermogenesis remain poorly understood. Here, we employed quantitative phosphoproteomics to map global and temporal phosphorylation profiles in brown, beige, and white adipocytes under β3-adrenenoceptor activation and identified kinases responsible for the adipose-selective phosphorylation profiles. We found that casein kinase2 (CK2) activity is preferentially higher in white adipocytes than brown/beige adipocytes. Genetic or pharmacological blockade of CK2 in white adipocytes activates the thermogenic program in response to cAMP stimuli. Such activation is largely through reduced CK2-mediated phosphorylation of class I HDACs. Notably, inhibition of CK2 promotes beige adipocyte biogenesis and leads to an increase in whole-body energy expenditure and ameliorates diet-induced obesity and insulin resistance. These results indicate that CK2 is a plausible target to rewire the β3-adrenenoceptor signaling cascade that promotes thermogenesis in adipocytes. Phosphoproteomics Identifies CK2 as a Negative Regulator of Beige Adipocyte Thermogenesis and Energy Expenditure. Kajimura et al 2015.

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