In vivo, knockout of SYK is incompatible with brown adipose formation, and we observed a strong counter selection for SYK proficient cells. We utilized numerous inhibitors, gene knock downs, and gene knockout strategies to show that SYK regulates activation, proliferation, and differentiation of brown adipocytes. Using a kinase inhibitor library, we show here that SYK is required for β-adrenergic stimulated upregulation of Ucp1 in mature brown adipocytes. Thus, SYK connects the BCR and other immune receptors with downstream activation of numerous pathways resulting in calcium release and transcriptional responses 9.Īlthough initially characterized as a hematopoietic cell-specific kinase essential for immune receptor signaling, SYK has been ascribed functions in other signaling cascades not only in immune cells but also in cells such as fibroblasts and endothelial cells 10. Recruitment of its paired SH2 domains to dually phosphorylated tyrosine binding motifs, termed immunoreceptor tyrosine based activation motifs (ITAMs), localizes SYK to ITAM linked receptors such as the B cell receptor (BCR) and activation of SYK is also mediated by Src-family tyrosine kinases such as Lck/Yes novel tyrosine kinase (LYN).
Spleen tyrosine kinase (SYK) is critical for survival, differentiation, and activation of several types of hematopoietic cells 9. Prolonged β-adrenergic stimulation induces proliferation and differentiation of brown adipocyte precursor cells, mitochondrial biogenesis, as well as changes in gene expression and browning of WAT to increase thermogenic capacity 7, 8. Rapid effects include increased nutrient uptake, lipolytic activation, and activation of UCP1. β-adrenergic stimulation, by cold or pharmacological agents, initiates numerous processes in the brown adipocytes aimed at increasing thermogenic activity and tissue recruitment. In WAT, cold exposure leads to the emergence of beige, or inducible brown, adipocytes 3.īrown adipocyte differentiation and activation in response to β-adrenergic stimulation can be modeled in vitro by inducing ex vivo isolated brown adipocyte precursors or precursor cell lines to assume a brown adipocyte-like phenotype, followed by stimulation with β-adrenergic agonists such as isoproterenol 4, 5, 6.
In BAT, cold exposure increases Ucp1 expression, mitochondrial biogenesis, and tissue expansion, resulting in an increase of thermogenic capacity 2. Cold exposure, through β-adrenergic signaling, induces changes in both tissues. On the other hand, brown adipose tissue (BAT), is specialized to generate heat and consume energy as a defense against cold BAT protects from excessive weight gain in response to overfeeding 1, 2.
Of the two principal types of adipose tissue, white adipose tissue (WAT) is specialized to store chemical energy in the form of triglycerides.
These results establish SYK as an essential mediator of brown fat formation and function.Īdipose tissue is an essential regulator of energy balance and nutritional homeostasis 1. SYK inhibition in vivo represses β-agonist-induced thermogenesis and oxygen consumption. Adipocyte-specific SYK deletion in mice reduces BAT mass and BAT that developed consisted of SYK-expressing brown adipocytes that had escaped homozygous Syk deletion. Deletion or inhibition of SYK, a kinase known for its essential roles in the immune system, blocks brown and white pre-adipocyte proliferation and differentiation in vitro, and results in diminished expression of Ucp1 and other genes regulating brown adipocyte function in response to β-adrenergic stimulation. Here we show that spleen tyrosine kinase (SYK) is upregulated during brown adipocyte differentiation and activated by β-adrenergic stimulation. Sympathetic stimulation of β-adrenergic receptors in response to cold induces proliferation, differentiation, and UCP1 expression in pre-adipocytes and mature brown adipocytes. Brown adipose tissue (BAT) metabolism influences glucose homeostasis and metabolic health in mice and humans.
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