Table 2.

A summary of InsR signaling in different neuronal subtypes

Neuronal subtypes	Transgenic approaches	Main findings	Physiological role	Ref.
ARC POMC neurons	POMC InsR KO POMC InsR KI mice POMC-eGFP POMC InsR/LepR double KO IRS2 KO mice	insulin depolarizes POMC neurons via activating TRPC5 channels and inhibits POMC neurons via PI3K activation IRS2 KO mice show lower POMC mRNA levels and higher levels of inflammation POMC InsR KO increased hepatic triglyceride levels in HFD mice overexpression of InsR in POMC neurons leads to increased energy expenditure and locomotor activity	Regulation of adipose lipolysis, neuronal plasticity, energy expenditure, glucose homeostasis and fertility	[47, 48, 50–52, 144–146]
ARC AgRP neurons	AgRP InsR KO AgRP InsR KI mice	increase in appetite, decrease in metabolism/energy expenditure restrained hepatic glucose production	Regulation of glucose metabolism	[47, 48]
LH MCH neurons	MCH InsR KO MCH-GFP MCH−/− mice	insulin increases excitability of MCH neurons MCH InsR KO mice showed no alterations in energy homeostasis or glucose metabolism in lean mice Increased hepatic insulin sensitivity in obese MCH InsR KO mice MCH ablation mice showed increased body weight and insulin resistance	Regulation of body weight, insulin sensitivity, and energy homeostasis	[53, 54, 147]
Orexin-A neurons	Orexin−/− mice Orexin-cre (DREADDs, viral ablation)	Orexin global KO leads to impaired hepatic insulin action manipulation of orexin neurons shows phenotypes in food intake and metabolism insulin i.c.v. injection activates orexin neurons Orexin A regulates plasma insulin levels	Prevention of hepatic insulin resistance Regulation of feeding behavior, metabolism	[56, 57, 148–150]
HPA axis	InsRNkx2.1 KO (hypothalamus) mice, InsRSim1 KO (PVN), mice InsRAgRP KO (ARH) mice	This study used separate Cre lines to achieve disruption of InsR signals in selective hypothalamic areas and found: InsRNkx2.1 KO leads to heightened HPA axis response to stress and anxiety-like behaviors in males InsRAgRP KO show reduced AVP release in median eminence	Regulation of HPA axis and stress response; Regulation of mood	[151]
Sensory neurons	Advillin-cre mice (SNIRKO)	no behavioral, physiological, or morphological signs of peripheral diabetic neuropathy elevated serum insulin levels, glucose intolerance, increased insulin in islets of pancreas	Regulation of islet function	[152]