Structural Biochemistry/Cell Signaling Pathways/Adipogenesis: From Stem Cell to Adipocyte

Overview

Adiposity and adipocyte hyperplasia are promoted by an excessive intake of calories without allowing energy expenditure to rise. This rise in the number of adipocyte is caused by signaling factors that are induced by mesenchymal stem cells conversion, also known as MSC. Mesenchymal stem cells are recruited from adipose tissues of vascular stroma. This provides adipocyte precursors an unlimited supply. Producing preadipocytes are committed by stem cell mediators from the members of Wnt and BMP families. Following this commitment, growth-arrested preadipocytes are exposed to inducers of differentiation. These inducers are cAMP, which are cyclic AMP, glucocorticoid, and IGF1, which is insulin-like growth factor. They can trigger replication of DNA and reenter into the cell cycle of mitotic clonal expansion. This expansion needs a cascade of transcription factor, followed by adipocyte gene expression. Phosphorylation of transcription factor gives rise to the activity of DNA-binding.

The Adipocyte

Origin: Adipocytes are developed pluripotent stem cells called MSCs. MSCs originated in adipose tissues as well as bone marrow, where development initially causes these cells to develop into preadipocytes. Upon evolving into preadiposites, the pre-specialized cells then go through mitosis several times via mitotic clonal expansion. With this expansion, there is a generation of many preadipocytes which eventually differentiate into fully functional adipocytes. One of the most studied preadipocytes is 3T3-L1, which is reliable in showing the historical transformation of the preadipocyte from a stem cell.

Adipocyte function: The adipocyte has endocrine-like functions such as the secretion of hormones and cytokines that directly influence bodily metabolism functions. These hormones include leptin, which helps the body limit energy storage once adipose tissues are at their maximum capacity, as well as adiponectin, which influences the hypothalamus in terms of digestive and food intake. Because adipocytes directly influence adipose tissue, adipocyte hormones also have an indirect influence over sympathetic nervous system hormones in the central nervous system, controlling hormones that regulate fat production (a cascading pathway).

Stem Cell To Preadipocyte

The stroma of adipose tissues contains a vast culture of MSC stem cells that have the ability to differentiate into functional adipocytes. Among the MSCs that can differentiate into adipocytes are C2H101/2, which also has the capability to differentiate into myocytes and osteocytes. Inhibitors and Promoters of Differentiation: BMP4 and BMP2 are bone morphogenetic proteins that have been known to help progress the MSC stem cells from developing into adipocytes (or at least preadipocytes). BMP4 allows for stem cells to turn into adipocytes by interfering with the DNA methylation process of stem cells, allowing for commitment of differentiation into adipocytes. On the other hand, Wnt10b inhibits the MSC stem cells from becoming an adipocyte due to the fact that Wnt10b differentiates the stem cell into osteogenesis/myogenesis (although some Wnt proteins have been known to help the stem cell commit into forming into an adipocyte). Another adipocyte formation inhibitor has been known to be Hh ligands, which performs Hedgehog signaling. Hedgehog signaling inhibits the formation of adipocytes by decreasing the amount of fat that can be stored in the cytoplasm, resulting in reduced fat mass and less of a need for new adipocytes.

Preadipocyte to Full Adipocyte

Induction: Preadipocytes are ready to fully differentiate into adipocytes when they reach their “growth arrest” state, also known as the G1 phase in the normal cell cycle. Inducers and inducing conditions, such as high concentrations of insulin, dexamethasone, and low IGF1 levels, then further differentiate the cell by activating a series of pathways, such as cAMP-signaling pathways, as well as glucocorticoids. With inducers, the “growth arrested” preadipocyte is forced back into the normal cell cycle, and continue to differentiate. By going through the cell cycle, the preadipocyte perofmes mitotic clonal expansion, further differentiating the cell. Upon completing the cell cycle once more, the preadipocyte loses their fibroblasts, and obtain cytoplasmic triglyceride as well as common traits as well as structures for a fully fledged adipocyte.

References

Adipogenesis: from stem cell to adipocyte. Tang QQ, Lane MD. Annu Rev Biochem. 2012;81:715-36. Epub 2012 Mar 29. Review.