Phosphoinositide 3-Kinase Is Integral for the Acute Activity of Leptin and Insulin in Male Arcuate NPY/AgRP Neurons

Abstract

Neuropeptide Y (NPY)/Agouti-related protein (AgRP) neurons in the arcuate nucleus of the hypothalamus are part of a neuroendocrine feedback loop that regulates feeding behavior and glucose homeostasis. NPY/AgRP neurons sense peripheral signals (including the hormones leptin, insulin, and ghrelin) and integrate those signals with inputs from other brain regions. These inputs modify both long-term changes in gene transcription and acute changes in the electrical activity of these neurons, leading to a coordinated response to maintain energy and glucose homeostasis. However, the mechanisms by which the hormones insulin and leptin acutely modify the electrical activity of these neurons remain unclear. In this study, we show that loss of the phosphoinositide 3-kinase catalytic subunits p110α and p110β in AgRP neurons abrogates the leptin- and insulin-induced inhibition of AgRP neurons. Moreover, continual disruption of p110α and p110β in AgRP neurons results in increased weight gain. The increased adiposity was concomitant with a hypometabolic phenotype: decreased energy expenditure independent of changes in food intake. Deficiency of p110α and p110β in AgRP neurons also impaired glucose homeostasis and insulin sensitivity. In summary, these data highlight the requirement of both p110α and p110β in AgRP neurons for the proper regulation of energy balance and glucose homeostasis.

Acute effects of zinc and insulin on arcuate anorexigenic proopiomelanocortin neurons

“…We then examined the effects of insulin on the membrane potential of arcuate NPY neurons (Supporting Information Figure S2A–D). Recent work suggests that the acute effects of insulin are widespread in NPY neurons (Huang et al ., ). In particular, NPY neurons were inhibited by insulin, regardless of their neurons expressing leptin protein (Huang et al ., ).…”

“…Recent work suggests that the acute effects of insulin are widespread in NPY neurons (Huang et al ., ). In particular, NPY neurons were inhibited by insulin, regardless of their neurons expressing leptin protein (Huang et al ., ). Consistent with previous reports (Huang et al ., ; Xu et al ., ), 9 of 13 NPY neurons from NPY‐hrGFP mice were hyperpolarized by −9.7 ± 0.9 mV in response to insulin (50 nM, Humulin‐R, Supporting Information Figure S2E,I) and four of seven NPY neurons were hyperpolarized by −11.9 ± 0.02 mV in response to insulin (50 nM, Sigma insulin, Supporting Information Figure S2G,I).…”

“…The 7–9 weeks pathogen‐free male POMC‐hrGFP::LepR‐cre::td‐tomato (POMC‐hrGFP mice RRID: IMSR_JAX:006421; LepR‐cre mice RRID: IMSR_JAX:008320; td‐tomato mice RRID: IMSR_JAX:007908) (He et al ., ; Huang et al ., ; Sohn and Williams, ; Williams et al ., ), POMC‐hrGFP::LepR‐cre::td‐tomato::TRPC5 KO (TRPC5 KO mice RRID: IMSR_JAX:030804) (Gao et al ., ), POMC‐creER::IR‐flox::LepR‐flox::td‐tomato (POMC‐CreER t2 mice RRID: MGI: 5569339, IR‐flox mice RRID: IMSR_JAX:006955, LpeR‐flox mice RRID: IMSR_JAX:018989) and NPY‐hrGFP mice (NPY‐hrGFP mice RRID: IMSR_JAX:006417) (Sun et al, ) were used for all experiments. All mice were housed under standard laboratory conditions (12 h on/off; lights on at 7:00 a.m.) and temperature‐controlled environment.…”

PI3K signalling in leptin receptor cells: Role in growth and reproduction

“…Likewise, the combined administration of p110α and p110β inhibitors blocked the acute anorexigenic action of leptin and insulin . Intact p110β or both p110α and p110β subunits in neurones expressing agouti‐related protein (AgRP) appear to be required for metabolic control . In SF1 neurones, distinct catalytic subunits are necessary for leptin or insulin cellular effects .…”

“…Another potential confounder is the expression of LR in neurones with distinct or opposite functions, such as the AgRP and POMC neurones in the arcuate nucleus. Previous studies have assessed the role of PI3K subunits in AgRP, POMC and other neuronal populations (ie, SF1) . Because only subsets of these neurones express LR, the results are ambiguous.…”