Regulation of the adipose tissue-brain axis by CTRP6 in response to short versus long-term caloric surplus

Obesity is the consequence of chronic exposure to a caloric intake that exceeds energy expenditure. When already established, obesity is associated with multiple alterations compared to the non-obese state. This multitude of co-occurring abnormal processes poses a major challenge to understand what initiates obesity-related disturbances that negatively affect health. In a previous BSF-funded project, we have demonstrated that the adipose (fat) tissue expression of CTRP6 – a gene that had been shown to be elevated in chronic obesity and regulate whole-body metabolism – rises very early upon exposure to an obesogenic (obesity-generating) diet. In fact, CTRP6 gene expression was elevated as early as after 3 days of initiating high-fat diet in mice. This was unique, as other genes thought to mediate the negative effects of adipose tissue in chronic obesity were still unchanged. Interestingly, while in this early response setting CTRP6 contributed to restraining weight gain, in chronic obesity it became a detrimental factor that contributed to metabolic dysfunction.

In recent years it became evident that another early response to obesogenic diet is inflammation in brain areas that regulate appetite and energy expenditure. This brain inflammation (neuroinflammation) is thought to drive subsequent weight gain. Thus, in the present proposal we questioned the role of CTRP6 in the early versus the prolonged response to an obesogenic diet. We propose to explore two major processes using mice and cells that do, or do not, express CTRP6: i. How CTRP6 shapes the adipose tissue response to short-term versus long-term high fat diet. We will employ a novel methodology that allows us to map adipose tissue at a single-cell level. This will enable us to document how CTRP6 shapes both changes in adipose tissue cellular composition and changes in the expression of genes that occur in a cell-type -specific manner. ii. The role of CTRP6 in the development of neuroinflammation. We will use cultured brain immune cells and whole mice to dissect out whether CTRP6 contributes to neuroinflammation directly (local production in the brain) versus its indirect role in the shaping of adipose tissue – brain axis. Results of this proposal will determine if CTRP6 is a significant player in the development of obesity. Furthermore, it will shed light on mechanisms that turn our body’s initial response to an obesogenic environment from protective (early on) to disruptive (when the obesogenic stimulus turns chronic).