Obesity and Diabetes

We seek to understand how patterns of fat development and the adaptation of adipose tissue to calorie excess impacts the development of systemic insulin resistance and Type 2 Diabetes Mellitus. We have discovered that post-natal fat plasticity – the ability to increase the generation of new fat cells in response to caloric stimulus – is lost in the adult mouse. The failure of a hyperplastic response to calorie excess is paradoxically associated with metabolic dysfunction, therefore suggesting that insulin resistance ensues in part due to a failure of new fat cell formation. Because fat cells arise from undifferentiated progenitor cells residing in adipose tissue, a major focus of the lab is to explore molecular determinants of progenitor self renewal and differentiation and to discover novel factors in the progenitor microenvironment that control the fate of adipocyte progenitors.

 

Metabolism of Starvation

The mechanisms responsible for the cellular and whole organismal adaptation to periods of nutrient deprivation or frank starvation are relevant to a range of diseases, including obesity and cancer. Having evolved in an evolutionary environment punctuated by feast and famine cycles, humans are extremely efficient at surviving and even thriving long periods in negative caloric balance. While some pathways that are activated in starvation conditions may be metabolically beneficial, the metabolic efficiency during periods of caloric deprivation may predispose humans to obesity. We utilize human fasting as a model, coupled with various discovery platforms including genome scale transcriptional profiling and metabolite profiling, to identify novel mediators of the starvation response, which we then study with reductionist methodologies in the laboratory.

 

Imaging mass spectrometry

We develop new methods to measure cell turnover and metabolism using stable isotope tracers and mass spectrometry. Stable isotopes are an ideal tool for measuring cell turnover and metabolism, because: (1) they are seamlessly incorporated by synthetic and metabolic pathways without cellular or organismal toxicity and (2) because mass spectrometry provides an avenue for their precise measurement in tissues, cells, or subcellular compartments. In addition to deployment of classical methods, such as Isotope Ratio Mass Spectrometry (IRMS), we have a major focus on a novel quantitative imaging platform called Multi-isotope Imaging Mass Spectrometry (MIMS), which enables measurement of stable isotope tracers in domains much smaller than a cubic micron. By coupling the measurement of stable isotopes with histologic images that approach the resolution of transmission electron microscopy, MIMS brings functional metabolic imaging to the level of the single cell and even the single organelle. Our current focus is on the application of MIMS to cancer metabolism and the mechanisms and functional significance of tumor metabolic heterogeneity. We are pursuing this goal utilizing a range of rodent tumor models (GEMS and xenografts) in parallel with translational studies in human cancer patients. MIMS analyses are conducted at the Brigham and Women’s Hospital Center for NanoImaging in Cambridge, which the PI, Matthew Steinhauser, directs. (hyperlink to CNI).

 

Human translation

A guiding principle of the laboratory is to leverage human observations to guide our reductionist studies – so called bedside-to-bench research. This larger guiding principle has taken a range of forms from leveraging data from large scale genetics studies accessed through collaborations to small translational studies conducted by members of our laboratory at the Brigham and Women’s Hospital Clinical Research Center. We are constantly exploring new approaches to bridging the clinical and basic sciences with the goal of increasing the relevance of our work to human health and disease.