Dynamic ’omics redefines how insulin signalling choreographs glucose metabolism
- University of Sydney, Sydney, Australia.
- RIKEN IMS, Yokohama, Japan.
- Keio University, Tsuruoka, Japan.
- University of Tokyo, Kashiwa, Japan.
Adipose (fat) tissue plays a crucial role in energy storage and release. Accordingly, adipose metabolism responds to fluctuating nutrient availability and hormonal cues. For instance, after a meal, insulin triggers a phosphorylation cascade to stimulate glucose uptake. This is considered insulin’s primary role, with subsequent energy storage activated by allostery as substrates accumulate. However, our recent phosphoproteomics screen in insulin-treated adipocytes identified hundreds of metabolic proteins - could insulin signalling play a role beyond glucose uptake, coercing glucose down specific metabolic routes? We addressed this by measuring acute, temporal metabolomic changes upon insulin exposure, taking a dynamic approach to traditional steady-state 13C-tracer-experiments. We found three exciting results: (1) Insulin rapidly stimulated glucose uptake (t1/2=4 min), with its kinetics explaining 48% of metabolomic changes in response to insulin. Indeed, glucose was necessary for insulin-stimulated lipogenesis and suppression of fatty-acid oxidation, suggesting glucose facilitates insulin action. (2) Despite this, flux analysis revealed glucose was primarily converted to lactate and favoured NADPH-generating pathways (e.g., pyruvate anaplerosis, pentose phosphate pathway). This is reminiscent of cancer metabolism. We believe this allows glucose to facilitate anabolism beyond being a mere carbon source in (terminally-differentiated) adipocytes. (3) Overlaying metabolomic and phosphoproteomic data (’transomic analysis’) revealed protein phosphorylation changed rapidly (<5 min), activating anabolism before substrates accumulated. Thus, insulin creates a demand-driven system to ’drag’ glucose down specific pathways. This complements supply-driven regulation of anabolism by substrate accumulation. Overall, this redefines how signalling coordinates metabolism, with implications for metabolic dysregulation in overactive signalling (cancer) or nutrient oversupply (diabetes).