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Objective Energy metabolism and insulin action follow a diurnal rhythm. It is therefore important that investigations into dysregulation of these pathways are relevant to the physiology of this diurnal rhythm. Methods We examined glucose uptake, markers of insulin action, and the phosphorylation of insulin signaling intermediates in muscle of chow and high fat, high sucrose (HFHS) diet-fed rats over the normal diurnal cycle. Results HFHS animals displayed hyperinsulinemia but had reduced systemic glucose disposal and lower muscle glucose uptake during the feeding period. Analysis of gene expression, enzyme activity, protein abundance and phosphorylation revealed a clear diurnal regulation of substrate oxidation pathways with no difference in Akt signaling in muscle. Transfection of a constitutively active Akt2 into the muscle of HFHS rats did not rescue diet-induced reductions in insulin-stimulated glucose uptake. Conclusions These studies suggest that reduced glucose uptake in muscle during the diurnal cycle induced by short-term HFHS-feeding is not the result of reduced insulin signaling., Highlights • Investigating metabolism in rodents over the diurnal cycle more accurately models normal animal physiology. • Diurnal regulation of substrate oxidation is altered in muscle of HFHS-fed rats. • There is a disconnect between glucose uptake and canonical insulin signaling in muscle. • Activation of Akt2 does not rescue diet-induced reductions in insulin-stimulated glucose uptake in muscle.

Objectives Insulin signaling in the brain has been implicated in the control of satiety, glucose homeostasis and energy balance. However, insulin signaling is dispensable in energy homeostasis controlling AgRP or POMC neurons and it is unclear which other neurons regulate these effects. Here we describe an ancient insulin/NPY neuronal network that governs energy homeostasis across phyla. Methods To address the role of insulin action specifically in NPY neurons, we generated a variety of models by selectively removing insulin signaling in NPY neurons in flies and mice and testing the consequences on energy homeostasis. Results By specifically targeting the insulin receptor in both fly and mouse NPY expressing neurons, we found NPY-specific insulin signaling controls food intake and energy expenditure, and lack of insulin signaling in NPY neurons leads to increased energy stores and an obese phenotype. Additionally, the lack of insulin signaling in NPY neurons leads to a dysregulation of GH/IGF-1 axis and to altered insulin sensitivity. Conclusions Taken together, these results suggest that insulin actions in NPY neurons is critical for maintaining energy balance and an impairment of this pathway may be causally linked to the development of metabolic diseases., Graphical abstract Image 1, Highlights • Insulin controls feeding via non-AgRP expressing NPY-neurons in flies and mice. • Energy expenditure is regulated by insulin responsive NPY neurons. • Insulin signaling in NPY neurons is required for maintaining whole body glucose homeostasis and insulin sensitivity. • Central insulin-NPY pathways regulate bone mass and growth development.

Insulin signaling in the brain has been implicated in the control of satiety, glucose homeostasis and energy balance. However, insulin signaling is dispensable in energy homeostasis controlling AgRP or POMC neurons and it is unclear which other neurons regulate these effects. Here we describe an ancient insulin/NPY neuronal network that governs energy homeostasis across phyla.To address the role of insulin action specifically in NPY neurons, we generated a variety of models by selectively removing insulin signaling in NPY neurons in flies and mice and testing the consequences on energy homeostasis.By specifically targeting the insulin receptor in both fly and mouse NPY expressing neurons, we found NPY-specific insulin signaling controls food intake and energy expenditure, and lack of insulin signaling in NPY neurons leads to increased energy stores and an obese phenotype. Additionally, the lack of insulin signaling in NPY neurons leads to a dysregulation of GH/IGF-1 axis and to altered insulin sensitivity.Taken together, these results suggest that insulin actions in NPY neurons is critical for maintaining energy balance and an impairment of this pathway may be causally linked to the development of metabolic diseases.