Molecular Mechanism of Brown Adipose Tissue Regression

Narrative: Currently, a substantial effort is focused on understanding the mechanisms regulating the induction of thermogenic beige adipocytes as a potential therapeutic target for increasing energy expenditure to reduce and/or prevent obesity and insulin resistance. Although humans have the capacity to induce thermogenic adipocytes, only 50% of adolescents and 10% of adults display cold inducible beige/brown adipocytes. In contrast, all humans are born with brown adipose tissue that begins to decline during the first decade of life and continues to decline throughout the normal lifespan. Similarly, brown adipose depots in mice decline both in mass and function starting at approximately 8-12 months of age and continue to decline throughout their remaining life span. Our preliminary data indicate that the decline brown adipose tissue mass and function results the activation of a Nlrp1 pyroptosis cell death pathway that is the focus of this new grant proposal.