Inter-organ communication through lipid derived metabolites
Adaptive Thermogenesis and Metabolic Disease
Heat production in response to cold exposure is an energetically demanding process. To fuel thermogenesis during cold exposure, brown adipocytes increase both glucose and lipid uptake. The unique capacity for thermogenic energy expenditure has made brown adipose tissue an attractive target for the treatment of obesity, type 2 diabetes, nonalcoholic fatty liver disease, and the metabolic syndrome, especially with the recent discovery that greater brown adipose mass in humans is inversely correlated with obesity.
The metabolic fuel that drives thermogenesis in brown fat is produced in peripheral tissues and must be transported into brown adipose tissue. The long-term focus of my research program is to understand the sources of lipids that fuel brown fat thermogenesis and uncover the cross-tissue communication pathways that regulate the production of these lipids. We will address these questions using lipidomics, genetics, and cellular and molecular biology techniques coupled with mouse physiology.
As a postdoctoral fellow, I discovered that acylcarnitines are necessary for maintaining body temperature during cold exposure (Figure 1). Cold exposure triggers the release of free fatty acids from white adipocytes, which then go to the liver to where they are substrates for acylcarnitine production and secretion into circulation. These excess acylcarnitines are then taken up by the brown adipose tissue and used to fuel thermogenesis.
The Simcox laboratory will focus on two unanswered questions:
1) How are liver-produced lipids taken up & metabolized in brown adipocytes?
Brown adipocytes increase uptake of circulating lipids 12-fold during cold exposure, but the contribution of the various lipid species to thermogenesis remains elusive. We will use heavy isotope and fluorescently labeled lipids to identify lipid importers, assess metabolic pathways of uptake, and characterize the functional importance of various lipid species in isolated brown adipocytes (Figure 2).
2) How is hepatic lipid processing regulated in cold exposure?
Hepatic lipid processing is required for mice to maintain their body temperature in response to cold exposure. In untargeted lipidomic analysis we identified several hundred hepatic lipids that are altered in cold exposure and correlate with changes in circulating lipids. We will functionally characterize the role of these lipids in cold exposure and identify the transcriptional programs that regulate their production and clearance.