Obesity has emerged as a significant underlying cause of various non-communicable diseases. What is worrisome is that most of the population in developed economies is overweight. Thus, there is a need to understand obesity better and find a medical solution to the condition. Adipocytes are critical regulators of energy balance and nutrient homeostasis. Obesity occurs due to the significant expansion of white adipose tissues (WAT). Studies show that there are two distinct kinds of WAT cells; those are subcutaneous (scWAT) and fat cells in the abdominal cavity or visceral (vsWAT). Further, studies show that most of the development of scWAT cells occurs in the prenatal period, and after that, they do not increase in numbers. On the contrary, vsWAT cell expansion occurs postnatally, and they play a vital role in the hyperplastic expansion of fat depots in response to high-calorie intake. However, what has perplexed researchers is why scWAT does not increase postnatally, and vsWAT does. Understanding this would help fight obesity and find effective treatments.
The sorting-related receptor with A-type repeats (SORL1) is a gene known to be associated with a higher risk of obesity. It encodes the type-1 transmembrane protein SORLA (also known as LR11), which plays the role of sorting receptor for insulin receptor (IR). Since the SORL1 gene and SORLA are known to be associated with visceral obesity, researchers tested the hypothesis that it is the reason why scWAT does not expand in adult life, but vsWAT does.
In a new study by Max-Delbrueck Center researchers and published in Journal of Cell Biology, Dr. Vanessa Schmidt and Dr. Thomas Willnow in collaboration with Dr. Carla Horváth, Dr. Hua Dong and Christian Wolfrum from the ETH Zurich in Switzerland, Dr. Matthias Blüher from the University of Leipzig and Dr. Per Qvist from the Aarhus University investigated the role of SORLA in obesity. Their studies confirmed the vital role SORLA plays in vsWAT expansion in response to a high-calorie diet in adult life and thus visceral obesity.
To start with, researchers compared the SORL1 expression level in scWAT and vsWAT of fat tissues of 362 adults extracted via biopsy. They found that SORL1 expression is much higher in vsWAT compared to scWAT. In humans, the vsWAT pool expands in response to a high-calorie diet. To understand if SORLA is responsible for this expansion, they studied genetically modified mice. For this, they used mice with SORL1 genetic deficiency in epididymal (ep) fat pats. On feeding them continually with a high-fat diet, they found that compared to control mice, a high-fat diet did not increase epWAT in SORLA deficient juvenile mice. In further analysis, they discovered that SORLA increases only the proliferation of epWAT, but not scWAT. They also found that deficiency of SORLA did not have much impact on the expansion of scWAT, but it impaired the proliferation of epWAT.
Additionally, in an in-vitro study using murine embryonic fibroblasts, the authors found that SORLA is required for insulin-dependent expansion of adipocyte precursor cells through mitosis. Furthermore, they reported that the level of SORLA defines how much adipocyte precursor cells respond to mitogenic stimuli from insulin.
Thus, In an elegant molecular and cellular experimental studies, the research team provided strong evidence regarding the role of the SORL1 gene in visceral obesity. SORL1 gene over-expression and a hence higher level of SORLA increase the mitotic expansion of vsWAT cells. Whereas low expression of SORLA means blunted response to insulin. At the same time, it appears that scWAT are more or less insensitive to SORLA in the postnatal period. These findings explain the genetic basis of SORLA expression and resulting visceral obesity and show that SORLA could be a druggable therapeutic target for fighting visceral obesity.
Schmidt, V., Horváth, C., Dong, H., Blüher, M., Qvist, P., Wolfrum, C., & Willnow, T. E. (2021). SORLA is required for insulin-induced expansion of the adipocyte precursor pool in visceral fat. The Journal of Cell Biology, 220(12), e202006058. https://doi.org/10.1083/jcb.202006058