Clinically we tell patient’s that weight loss is about mindset, but I’ve struggled explaining the biochemical pathway why epinephrine associated with stress would cause insulin resistant patients to gain weight, rather than lose weight.
1. Chronic elevated stress responses lead to elevated epinephrine.
2. Epinephrine normally signals for the conversion of fat into energy as animals run from predators, or into body heat when they get cold, producing weight loss due to lipid mobilization. This β-adrenergic receptor activation increases activity of protein kinase A (PKA) and leads to phosphorylation of adipocyte lipases, such as hormone-sensitive lipase and lipolysis.
3. The adipocyte also has a cell surface receptor (immunoglobulin superfamily molecule) for advanced glycation end (RAGE) products. RAGE is activated by carboxymethyllysine (CML)-advanced glycation end products (AGEs), high-mobility group box 1 (HMGB1), and S100/calgranulins, which accumulate in metabolic stress. All of these compounds are seen in aging, diabetic and obese patients.
4. Activating the RAGE receptor, even in the presence of epinephrine, causes inhibition of hormone-sensitive lipase and lipolysis.
5. In effect, RAGE blocks the “fat burning” called for when we starve, freeze, get injured, panic, or ironically, overeat. RAGE is turned on by the advanced glycation end products (AGEs), which form when blood sugar combines with proteins or fat, preventing the normal action of epinephrine.
RAGE is a critical link between the metabolism, immune function, and stress.
A Receptor of the Immunoglobulin Superfamily Regulates Adaptive Thermogenesis. Cell Reports, 2019; 28