Molecule that is capable to cure obesity

The obesity epidemic is growing every year, and science has long been trying to find a way to treat obesity. At the same time, the functioning of adipose tissue is strongly influenced by the immune system. For example, some type 2 immune cells can activate the metabolism of fat cells while others conversely stimulate adipocyte’s insulin sensitivity (insulin signal promotes fat storage) [1-4]. Therefore, researchers looking for a cure for obesity are paying particular attention to the effects of the immune system on adipose tissue. So, scientists from Perelman School of Medicine at the University of Pennsylvania together with colleagues studied how thymic stromal lymphopoietin (TSLP) affects adipose tissue [5].

TSLP is a mediator secreted by epithelial cells that activates various immune cells [6]. The authors of the study inserted into the liver cells of experimental mice a gene by which TSLP is synthesized, and tested how this modification would affect the obesity of experimental animals. TSLP effect was tested in groups of mice that developed obesity for very different reasons (due to high-fat diet, genetic factors, insulin resistance of liver dysfunction). And in all groups, TSLP led to the loss of white adipose tissue (the storage of lipids) independently of the cause of obesity. Moreover, TSLP acted selectively: any effect of TSLP on brown adipose tissue (it generates heat) and muscles was not noticed. And TSLP also improved the metabolism of fats and carbohydrates in experimental animals in general.

Researchers tried to find the mechanism of TSLP-induced weight loss and found that it was not about increasing energy expenditure and decreasing calorie intake of the mice. They noticed instead that the hair of the experimental mice became greasy. After analyzing the sebum of the mice, scientists realized that fat disappears from their bodies through the skin, or rather, through the sebaceous glands. And the main work was done by sebocytes — cells that, gradually collapsing, release sebum particles to the outside. Then sebum secreted by sebocytes comes out to the surface of the skin through the canal of the hair follicle (which is why the hair became greasy). It turned out that due to the immune cell-mediated action of TSLP, sebocytes were destroyed faster and renewed more often.

As it turned out, TSLP directly altered the activity of CD4+ or CD8+ through their receptors, as a result of which these T-cells rushed into the skin and stimulated sebocytes there. On the one hand, it is surprising that the main effect of TSLP was mediated by cells that were so much different from what was expected. On the other hand, this effect could be expected because sebum, which contains bactericidal fatty acids and antimicrobial peptides, is an important external physical and immune-protective barrier of the body [7, 8]. And therefore, sebum secretion is indeed regulated by immune cells that TSLP activates.

The method of treating obesity by injecting a viral vector with the TSLP gene needs to be tested whether TSLP will help people and whether it will be safe for them. And if treatment with TSLP proves to be effective for humans, then obese people will be able to get rid of white adipose tissue weighing 0.5 kg or more per week with ease.

Alexander Khazanov

References:

1. Qiu, Yifu, et al. “Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat.” Cell 157.6 (2014): 1292-1308.
2. Brestoff, Jonathan R., et al. “Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity.” Nature 519.7542 (2015): 242-246.
3. Lee, Min-Woo, et al. “Activated type 2 innate lymphoid cells regulate beige fat biogenesis.” Cell 160.1-2 (2015): 74-87.
4. Feuerer, Markus, et al. “Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters.” Nature medicine 15.8 (2009): 930-939.
5. Choa, Ruth, et al. “Thymic stromal lymphopoietin induces adipose loss through sebum hypersecretion.” Science 373.6554 (2021).
6. Ziegler, Steven F., and David Artis. “Sensing the outside world: TSLP regulates barrier immunity.” Nature immunology 11.4 (2010): 289-293.
7. Lovászi, Marianna, et al. “Sebaceous-immunobiology is orchestrated by sebum lipids.” Dermato-endocrinology 9.1 (2017): e1375636.
8. Lee, Dong-Youn, et al. “Sebocytes express functional cathelicidin antimicrobial peptides and can act to kill propionibacterium acnes.” The Journal of investigative dermatology 128.7 (2008): 1863.