Understanding the molecular mechanism in failure of osteoblast-mediated repair for articular bone erosion during progressive rheumatoid arthritis: Role of casein kinase-2 interacting protein-1 in controlling osteoblast function

Obesity has become a public health crisis. Obese people are predisposed to a number of diseases, including cardiovascular disease, type 2 diabetes, hypertension, stroke and many types of cancers. Strategy to enhance energy expenditure and combat the epidemic of obesity is desperately needed.

There are two types of adipocytes, white adipocyte and brown adipocyte. White adipocytes are specialized to store chemical energy while brown adipocytes dissipate energy as heat. Uncoupling protein 1 (UCP1) is an integral membrane protein unique to the mitochondria in brown adipocyte and is responsible for respiratory uncoupling during thermogenesis. However, the active brown fat is virtually absent or has low thermogenesis activity in obese people.

“Browning” - to induce white adipocytes to express UCP1 and other brown adipocyte phenotypes and properties - is regulated by adrenergic stimulation and cycloxygenase (COX) activity. Consumption of a common, natural and non-toxic herbal extract to achieve browning effect is an attractive anti-obesity strategy.

Our preliminary data showed that cinnamon extract (CE) treatment (i) induced brown adipocyte typical multiocular phenotypes and UCP1 expression in differentiated 3T3-L1 white adipocytes in vitro, (ii) induced UCP1 expression in subcutaneous adipose tissue and subcutaneous adipocytes isolated in db+/+db, m+/+db mice, as well as (iii) in diet-induced obesity (DIO) mice ex vivo. Besides, norepinephrine also induced UCP1 expression in the subcutaneous adipocytes ex vivo. Moreover, (iv) CE treatment increased cyclooxygenase 2 (COX2) expression in subcutaneous adipose tissue and subcutaneous adipocytes isolated in db+/+db and DIO mice; selective COX2 inhibitor, celecoxib, reduced the CE-induced UCP1 expression. (v) In lipidomic study, we have revealed potential prostaglandins that might mediate the browning effect of CE in subcutaneous adipocytes. Taken together, we hypothesize that CE signals through COX2 and β-adrenergic pathways to upregulate UCP1 and mediate browning effect in subcutaneous adipocytes.

To test the hypothesis, we aim (1) to examine if COX2 (and/or COX1) mediates CE effects on browning; (2) to test whether our identified prostaglandins mediate CE effects on browning. Furthermore, we aim (3) to test whether β-adrenergic signaling mediates the CE effects on browning. We will also test an alternative pathway in which a direct activation of Transient Receptor Potential A1 (TRPA1) channel by cinnamaldehyde, an active component in CE, causes the browning effects.

If the hypothesis is supported, it will lay the foundation for in-depth study of the CE browning effect in vivo and its effect on obese mouse metabolism.