1. The effects of diet-induced obesity on hematopoiesis

In order to understand the source of inflammation we have focused on understanding changes within the hematopoietic compartment. The prominent white blood cell increased and activated during obesity is the macrophage. We have focused our studies on looking at the generation of myeloid cells (macrophages and neutrophils) and how this is enhanced in the bone marrow of obese mice. These changes are sustained even after bone marrow transplantation and weight loss. By investigating the changes within these progenitors we will gain knowledge and understanding of the long-term persistent impact of diet-induced obesity on the immune system.

2 . Sex differences in diet-induced inflammation

Many diseases are known to have sexually dimorphic prevalence or severity. One example of this is cardiovascular and metabolic diseases, which have higher prevalence rates in males and lower rates in reproductive aged women. There are also significant differences in disease presentation and it is becoming clear that different management strategies are needed.

We have profiled the differences in male and female inflammatory responses to high fat diets and have found that males have increased macrophage production and activation whereas females are protected from this. Further studies are focused on understanding what leads to these sex differences and what are the clinical implications of these different inflammatory responses in males and females.

3. Effects of obesity on the bone marrow environment

In order to understand what drives enhanced myelopoiesis we are now focusing on investigating changes within the bone marrow compartment and the relationship between other cell types in the niche, including bone and marrow adipose tissue.

5. Investigating lipolysis as a mechanism driving sex differences in inflammation in old mice

Aging is another model tightly associated with inflammation where declining estrogen levels in older menopausal women and increased visceral fat accumulation pose a greater risk for CVD and diabetes than younger women. However, the metabolic factors regulating the sex differences in the inflammatory response remain unclear. Fat stored in adipose tissues is released through lipolysis and utilized via beta-oxidation in times of energy demand. Altered lipolysis can create an imbalance in fat storage and utilization leading to lipotoxicity that might be a possible trigger for inflammation. We therefore focus on a stimulated lipolysis model in old and obese mice to study sex differences in inflammatory responses. We thereby assess the effects of excess free fatty acids on adipose tissue macrophage (ATM) accumulation.

6. Effect of obesity on bacterial infection responses.

Obesity can modify patient outcomes in critical illness. In fact, in what is commonly referred to as the "obesity paradox", data suggests a potential improved clinical outcome. However, recent studies have found a link between obesity and increased morbidity and mortality with impaired responses to bacterial infection including localized infections and systemic sepsis. We have found that diet induced obesity modifies macrophage phenotype and we are further evaluating the influence of body composition on sepsis and immune responses to bacterial infection to gain a better understanding of the mechanisms of impairment. We are further working to understand the local leukocyte response within the lung to bacterial infection.