Ongoing Research
Projects
The central goal of our research is to make profound impacts on our understanding and treatment of common metabolic diseases through continuous innovation. Our research approaches thrive at the interface of disciplines such as biology, chemistry, and
bioengineering and are driven by a highly collaborative team science approach. The lab’s initial emphasis has been on the role of protein mediated fatty acid uptake
included identification of the first intestinal fatty acid transporter (FATP), demonstrating the existence of an insulin-sensitive fatty acid transporter in adipocytes, and to identify a liver-specific FATP. This research evolved into wider approach to leverage stem cell and
bioengineering based approaches together with physiology and cell biology to understand adipocyte and liver biology and interorgan communication. We have been pioneering investigations into the role of biomechanical forces in brown adipose tissue (BAT) activation and are working on novel lipid nanoparticle-based approaches to expand and activate BAT.
Further, the Stahl lab is developing New Approach
Methodologies (NAM) based on human induced pluripotent stem cell-derived microphysiological systems, aka organ-on-a-chip devices, particularly for the functional interrogation of the fat-liver axis. The lab’s current focus with these NAMs is to facilitate
the assessment of biological mechanisms, such as aging, and diseases, including T2DM and MASLD, as well as testing of pharmacological intervention strategies, in the context of human- has been pioneering investigations into the role of biomechanical
forces in brown adipose tissue (BAT) activation and is working on novel lipid nanoparticle-based approaches to expand and activate BAT. Further, Dr. Stahl’s lab is
developing New Approach Methodologies (NAM) based on human induced pluripotent stem cell derived microphysiological systems, aka organ-on-a-chip devices, particularly for the functional interrogation of the fat-liver axis. The lab’s current focus with these NAMs is to facilitate the assessment of biological mechanisms, such as aging, and diseases, including T2DM and MASLD, as well as testing of pharmacological intervention strategies, in the context of human relevant preclinical models.
relevant preclinical models.
Nutrient Transport, Imaging, and Redox Biology
In order to visualize changes in organismal lipid fluxes as well as other macro and micronutrient, such as copper, we developed novel imaging probes in conjunction with Drs. Bertozzi, Dubikovskaya, and Chang. We showed that a bioluminescent copper and fatty acid probes can be utilized in live animals for the quantitative spatio-temporally resolved detection of hepatic copper and fatty acid fluxes and now have leveraged this technology to determine changes in lipid utilization during the development of hepatocellular- and cholangiocarcinomas. To this end, we utilized hydrodynamic transfection of specific oncogene combinations in conjunction with in vivo imaging as well as tumor-specific in vivo CRISPR/Cas9 gene ablation to uncover novel metabolic vulnerabilities of hepatic carcinomas. In a recent collaboration with Dr. Dubikovskaya,we also developed and tested a novel imaging probe for Coenzyme Q (CoQ) and demonstrated dependence on CD36 for cellular Coenzyme Q uptake. This interest in CoQ biology in our lab led to the finding that CoQ required for thermogenic activity in BAT. CoQ deficiency leads to a wide range of pathological manifestations, but mechanistic consequences of CoQ deficiency in specific tissues such as BAT remain poorly understood. Current research by our team is showing that pharmacological or genetic CoQ deficiency (50-75% reduction) in BAT leads to accumulation of cytosolic mitochondrial RNAs (mtRNAs) and activation of the eIF2α kinase PKR resulting in activation of the integrated stress response (ISR) and suppression of UCP1 expression in an ATF4-dependent fashion. Surprisingly, despite diminished UCP1 levels, BAT CoQ deficiency increases whole-body metabolic rates at room temperature and thermoneutrality resulting in decreased weight gain on high fat diets (HFD). This mitohormesis-like effect is dependent on the ATF4-FGF21 axis in BAT revealing an unexpected role for CoQ in the modulation of whole-body energy expenditure with wide-ranging implications for primary and secondary CoQ deficiencies.
Adipose Mechanobiology
Brown and beige adipocytes are thermogenic adipocytes that dissipate energy as heat through uncoupled mitochondrial respiration mediated by uncoupling protein 1 (UCP1). When the organism experiences cold exposure, brown and beige adipocytes can be activated in response to β-adrenergic stimulation, classically through PKA-CREB cascade and upregulate UCP1
expression. Recent work from our lab has revealed that, in addition to this canonical signaling pathway, β-adrenergic stimulation induces actomyosin-driven intracellular tension in both brown and beige adipocytes. This mechanically regulated response is not only correlative but also required for full thermogenic activation. Notably, further mechanistic search uncovered distinct downstream pathways by which these two types of thermogenic adipocytes sense and transduce actomyosin-mediated tension: while brown adipocytes primarily signal through the YAP/TAZ axis, beige adipocytes’ response to β-adrenergic driven tension changes depends on focal adhesion kinase (FAK) activity.
Microphysiological Systems
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