Linda Engström Ruud

Highlights • Chemo- or optogenetic activation of GFRAL+ neurons causes hypothermia • Acute GFRAL+ neuron activation stimulates lipid oxidation and ketogenesis • Such activation impairs skeletal muscle insulin sensitivity, resulting in hyperglycemia • GDF15 treatment acutely lowers body temperature and glucose oxidation Summary GFRAL-expressing neurons actuate aversion and nausea, are targets for obesity treatment, and may mediate metformin effects by long-term GDF15-GFRAL agonism.

Abstract Activation of Agouti-Related Peptide (AgRP)-expressing neurons promotes feeding and insulin resistance. Here, we examine the contribution of neuropeptide Y (NPY)-dependent signaling to the diverse physiological consequences of activating AgRP neurons. NPY-deficient mice fail to rapidly increase food intake during the first hour of either chemo- or optogenetic activation of AgRP neurons, while the delayed increase in feeding is comparable between control and NPY-deficient mice.

Mouse experiments Study consideration and design The circadian clock impacts on almost all metabolic pathways in the murine liver and ER-stress networks have a periodicity of 12 hr with lowest activity mid through the light cycle (Zeigtgeber, ZT6) ( Cretenet et al., 2010 Cretenet G. Le Clech M. Gachon F. Circadian clock-coordinated 12 Hr period rhythmic activation of the IRE1alpha pathway controls lipid metabolism in mouse liver.Cell Metab. 2010; 11: 47-57 ).