Insulin controls food intake and energy balance via NPY neurons

Abstract

ObjectivesInsulin 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.MethodsTo 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.ResultsBy 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.ConclusionsTaken 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.

Inhibition of Adenosine Monophosphate–Activated Protein Kinase–3‐Hydroxy‐3‐Methylglutaryl Coenzyme A Reductase Signaling Leads to Hypercholesterolemia and Promotes Hepatic Steatosis and Insulin Resistance

“…Glucose and insulin tolerance tests were performed on 6‐hour‐fasted or 4‐hour‐fasted mice that were administered intraperitoneally with glucose (1 mg/g body weight) or insulin (0.5 mU/g body weight), respectively. Blood glucose levels were assessed at 0, 15, 30, 60, and 90 minutes after glucose administration using an Accu‐Chek Go glucometer (Roche) as described …”

A Promising Therapeutic Target for Metabolic Diseases: Neuropeptide Y Receptors in Humans

“…These diseases are caused by long-term energy metabolism disequilibrium, together with an imbalance between energy intake and energy expenditure. Studies have revealed that NPY is a major regulator in balancing energy metabolism [26, 94, 95] and resists excessive loss of fat by lipolysis in calorie-restricted mice indicating a trait potential for the life-extending effect of calorie restriction [95]. The NPY receptors, as is reported, can regulate energy balance and body weight in a cooperative manner.…”

“…Pre-diabetes is characterized by hyperinsulinemia, impaired glucose tolerance, as well as insulin resistance which is associated with the dysfunctional islet beta cells [108]. Previous studies demonstrated that in diabetes models, NPY exerts a profound role in the regulation of blood glucose homeostasis [26]. Insulin acts on NPY neurons and modulates the balance of energy regulation and the dysfunction of which may result in the development of metabolic diseases.…”

“…Different Y receptors mediate different processes and diseases such as food intake [17], obesity, hypertension, atherosclerosis, epilepsy, metabolic disorders, fracture healing [18] and many cancers [19-26]. By binding to different receptors，NPY plays various roles in human biological processes, and sometimes can even function quite differently.…”

Mutual Relationship between Tau and Central Insulin Signalling: Consequences for AD and Tauopathies?

“…Selective inactivation of IR in these neurons showed that AgRP neurons, rather than POMC neurons are required for central insulin control of hepatic glucose production [18]. In the same manner, inactivation of IRs in NPY-expressing neurons induced an obese phenotype, leading to the conclusion that insulin signalling in NPY neurons controls food intake and energy expenditure [37]. Furthermore, insulin decreases expression of the orexigenic peptides AgRP and NPY, leading to decreased food intake and increased expression of POMC [38], resulting in increased levels of α-MSH, which promotes anorexia and increases energy expenditure [39].…”