Brain-derived Neurotrophic Factor in Adipose Tissue

Obesity and type 2 diabetes are conditions that lead to adipocyte hypertrophy and inflammation due to metabolic dysfunction. Proper neural innervation of adipose tissue is important for metabolic control. Brain-derived neurotrophic factor (BDNF) is a growth factor that we have identified in the stromovascular fraction of adipose tissue; it is secreted from the immune cells that reside alongside adipocytes within a fat depot. Neurotrophic factors promote neuron survival and plasticity, but the role of BDNF in adipose tissue is not understood. Using a transgenic mouse model (LysM-cre x BDNF flox) we knocked-out (KO) BDNF in myeloid lineage immune cells, a group that includes macrophages, which we predict secrete BDNF. We confirmed that this LysM-Cre-mediated deletion of BDNF resulted in a genetic denervation of subcutaneous white adipose tissue, but not other peripheral nerves.
By comparing effects of cold-stimulation (promotes neural activation and lipolysis) with high-fat diet (promotes adipose tissue hypertrophy), we have demonstrated that the BDNF KO mice are unable to properly mediate adipose tissue function. We have also demonstrated that the KO mice display the presence of cold-induced brown adipocytes in the subcutaneous fat depot (‘browning’), but the brown adipocyte thermogenic marker uncoupling protein 1 (UCP1) is absent in these cells, likely because it requires neural innervation/activation to be turned on. We are currently employing tissue clearing protocols and whole-mount immunostaining in adipose depots from KO and control mice to determine how macrophages and adipocytes are innervated and to clarify the relationship between macrophages, BNDF secretion and sympathetic nerve-induced ‘browning’.

Faculty Mentor: Kristy Townsend