A Purdue University study shows that Notch signaling, a key biological pathway tied to development and cell communication, also plays an important role in the onset of obesity and Type 2 diabetes, a discovery that offers new targets for treatment.
A research team led by Shihuan Kuang, associate professor of animal sciences, found that blocking Notch signaling in the fat tissue of mice caused white fat cells to transform into a "leaner" type of fat known as beige fat. The finding suggests that suppressing Notch signaling in fat cells could reduce the risk of obesity and related health problems, Kuang said.
"This finding opens up a whole new avenue to understanding how fat is controlled at the molecular level," he said. "Now that we know Notch signaling and obesity are linked in this way, we can work on developing new therapeutics."
The human body houses three kinds of fat: white, brown and beige. White fat tissue stores fatty acids and is the main culprit in weight gain. Brown fat, which helps keep hibernating animals and infants warm, burns fatty acids to produce heat. Humans lose most of their brown fat as they mature, but they retain a similar kind of fat - beige fat, which also generates heat by breaking down fatty acids.
Buried in white fat tissue, beige fat cells are unique in that they can become white fat cells depending on the body's metabolic needs. White fat cells can also transform into beige fat cells in a process known as browning, which raises the body's metabolism and cuts down on obesity.
Kuang and his team found that the Notch signaling pathway inhibits browning of white fat by regulating expression of genes that are related to beige fat tissue.
"The Notch pathway functions like a commander, telling the cell to make white fat," he said.
Suppressing key genes in the Notch pathway in the fat tissue of mice caused them to burn more energy than wild-type mice, reducing their fat mass and raising their metabolism. The transgenic mice stayed leaner than their wild-type littermates even though their daily energy intake was similar, Kuang said. They also had a higher sensitivity to insulin, a lower blood glucose level and were more resistant to weight gain when fed a high-fat diet.
Pengpeng Bi, a doctoral candidate in animal sciences and first author of the study, said that the transgenic mice's body fat appeared browner upon dissection than the fat in wild-type mice, suggesting that blocking the Notch pathway had increased the number of their beige fat cells.
"Otherwise they looked normal," he said. "We did not notice anything exceptional about them until we looked at the fat."
Kuang and his team found that giving obese mice dibenzazepine, a drug that suppresses the Notch signaling pathway, reduced their obesity and improved their glucose balance.
Because the Notch signaling pathway is very similar in mice and humans, Kuang sees the results as having important implications for treating obesity and Type 2 diabetes in humans.
Type 2 diabetes, formerly known as "adult-onset diabetes," is a chronic ailment that particularly affects people who are overweight, lead sedentary lifestyles or have poor nutrition.
"This gives us new targets in the fight against obesity," Kuang said. "Inhibiting genes in the Notch pathway can convert white fat into beige and could reverse some of the effects of diabetes by renewing the body's sensitivity to insulin."
The study was published in Nature Medicine and is available at http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.3615.html.
The research was funded in part by the National Institutes of Health.
Writer: Natalie van Hoose, 765-496-2050, email@example.com
Sources: Shihuan Kuang, 765-494-8283, firstname.lastname@example.org
Pengpeng Bi, 765-494-8280, email@example.com
Inhibition of Notch signaling promotes browning of white adipose tissue and ameliorates obesity
Pengpeng Bi 1; Tizhong Shan 1; Weiyi Liu 1; Feng Yue 1; Xin Yang 1; Xin-Rong Liang 1; Jinghua Wang 1; Jie Li 2; Nadia Carlesso 4; Xiaoqi Liu 2, 3; Shihuan Kunag 1, 3
1 Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA
2 Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA
3 Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA
4 Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Beige adipocytes in white adipose tissue (WAT) are similar to classical brown adipocytes in that they can burn lipids to produce heat. Thus, an increase in beige adipocyte content in WAT browning would raise energy expenditure and reduce adiposity. Here we report that adipose-specific inactivation of Notch1 or its signaling mediator Rbpj in mice results in browning of WAT and elevated expression of uncoupling protein 1 (Ucp1), a key regulator of thermogenesis. Consequently, as compared to wild-type mice, Notch mutants exhibit elevated energy expenditure, better glucose tolerance and improved insulin sensitivity and are more resistant to high fat diet-induced obesity. By contrast, adipose-specific activation of Notch1 leads to the opposite phenotypes. At the molecular level, constitutive activation of Notch signaling inhibits, whereas Notch inhibition induces, Ppargc1a and Prdm16 transcription in white adipocytes. Notably, pharmacological inhibition of Notch signaling in obese mice ameliorates obesity, reduces blood glucose and increases Ucp1 expression in white fat. Therefore, Notch signaling may be therapeutically targeted to treat obesity and type 2 diabetes.
Natalie van Hoose | Eurek Alert!
GLUT5 fluorescent probe fingerprints cancer cells
20.04.2018 | Michigan Technological University
Scientists re-create brain neurons to study obesity and personalize treatment
20.04.2018 | Cedars-Sinai Medical Center
Physicists at the Laboratory for Attosecond Physics, which is jointly run by Ludwig-Maximilians-Universität and the Max Planck Institute of Quantum Optics, have developed a high-power laser system that generates ultrashort pulses of light covering a large share of the mid-infrared spectrum. The researchers envisage a wide range of applications for the technology – in the early diagnosis of cancer, for instance.
Molecules are the building blocks of life. Like all other organisms, we are made of them. They control our biorhythm, and they can also reflect our state of...
University of Connecticut researchers have created a biodegradable composite made of silk fibers that can be used to repair broken load-bearing bones without the complications sometimes presented by other materials.
Repairing major load-bearing bones such as those in the leg can be a long and uncomfortable process.
Study published in the journal ACS Applied Materials & Interfaces is the outcome of an international effort that included teams from Dresden and Berlin in Germany, and the US.
Scientists at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) together with colleagues from the Helmholtz-Zentrum Berlin (HZB) and the University of Virginia...
Novel highly efficient and brilliant gamma-ray source: Based on model calculations, physicists of the Max PIanck Institute for Nuclear Physics in Heidelberg propose a novel method for an efficient high-brilliance gamma-ray source. A giant collimated gamma-ray pulse is generated from the interaction of a dense ultra-relativistic electron beam with a thin solid conductor. Energetic gamma-rays are copiously produced as the electron beam splits into filaments while propagating across the conductor. The resulting gamma-ray energy and flux enable novel experiments in nuclear and fundamental physics.
The typical wavelength of light interacting with an object of the microcosm scales with the size of this object. For atoms, this ranges from visible light to...
Stable joint cartilage can be produced from adult stem cells originating from bone marrow. This is made possible by inducing specific molecular processes occurring during embryonic cartilage formation, as researchers from the University and University Hospital of Basel report in the scientific journal PNAS.
Certain mesenchymal stem/stromal cells from the bone marrow of adults are considered extremely promising for skeletal tissue regeneration. These adult stem...
13.04.2018 | Event News
12.04.2018 | Event News
09.04.2018 | Event News
23.04.2018 | Physics and Astronomy
23.04.2018 | Physics and Astronomy
23.04.2018 | Trade Fair News