| Obesity and the metabolic syndrome have become leading causes of morbidity and mortality in the United States and worldwide. Although it is widely appreciated that obesity is closely associated with development of other metabolic diseases such as atherosclerosis, non-alcoholic fatty liver disease and type 2 diabetes mellitus, there is currently no unifying model for how this progression occurs. One widely studied hypothesis that has emerged is that obesity induces a state of low-grade chronic inflammation that induces foam cell formation in the arteries, steatohepatitis in the liver, and insulin resistance in liver and skeletal muscle. Investigation into this model has uncovered myriad ways in which cells and molecules of the immune system can impact metabolic functions. However, it has also led to substantial disagreement between experts in metabolism and inflammation, at least in part because inflammation in metabolism does not appear to follow the known rules of the immune system. Such discourse is colored by biases from both fields, and makes it clear that substantial revision may be required in how we understand our physiology.;"Immunometabolism" has presented far more questions than it has answers. Two of the major questions are: Can and does the immune system impact normal metabolic physiology, as it does pathophysiology? And what are the various cells and functions that are involved and how are they orchestrated (by what set of rules) in metabolic health and disease?;Caspase-1 is a component of the innate immune system that can be activated by numerous stimuli and leads to effects ranging from cytokine secretion to cellular repair to cell death. Its role has been best studied in the context of intracellular infections, where it is used to kill its macrophage host in order to limit the spread of infection. In the second chapter of this thesis, we present work showing that mice deficient in caspase-1 have substantially altered lipid metabolism even in a healthy, uninfected and un-immunized state, when activity of the enzyme cannot be detected by traditional methodologies. Moreover, this phenotype appears to be attributable to a non-hematopoietic cell type, rather than to macrophages. These data suggest that caspase-1 can operate at low levels in multiple cell types under steady-state conditions, and that this low level of activity is sufficient to enact significant changes in metabolic physiology. Moreover, it suggests that pharmacologic suppression of caspase-1 activity could be beneficial in reducing dyslipidemia in human patients.;CD1d is a lipid-presenting MHC-like molecule that leads to the activation of CD1d-restricted cells, predominantly invariant natural killer T cells (iNKTs). While many cells and molecules of the immune system that have no obvious connection with metabolite sensing appear to be activated in obesity, the role of these lipid sensors in metabolism has not previously been investigated to our knowledge. Here, we present evidence that CD1d, independently of iNKTs, subtly influences hepatic lipid transport or metabolism and partially protects from steatosis-associated hepatic insulin resistance as a result. This suggests that CD1d may play dual roles in the immune system and in metabolism and blurs the line between these two systems. |
