PI3K integrates the action of insulin and leptin on hypothalamic neurons

Abstract

Central control of energy balance depends on the ability of proopiomelanocortin (POMC) or agouti-related protein (Agrp) hypothalamic neurons to sense and respond to changes in peripheral energy stores. Leptin and insulin have been implicated as circulating indicators of adiposity, but it is not clear how changes in their levels are perceived or integrated by individual neuronal subtypes. We developed mice in which a fluorescent reporter for PI3K activity is targeted to either Agrp or POMC neurons and used 2-photon microscopy to measure dynamic regulation of PI3K by insulin and leptin in brain slices. We show that leptin and insulin act in parallel to stimulate PI3K in POMC neurons but in opposite ways on Agrp neurons. These results suggest a new view of hypothalamic circuitry, in which the effects of leptin and insulin are integrated by anorexigenic but not by orexigenic neurons. IntroductionControl of energy homeostasis requires the central nervous system to sense and respond to changes in peripheral energy stores. Among first-order neurons suggested to date are those found in the hypothalamic arcuate nucleus that express either proopiomelanocortin (POMC) or agouti-related protein (Agrp), neuropeptides that promote negative and positive energy balance, respectively. The activity of these neurons is regulated in a reciprocal manner by leptin, an adipocyte-derived hormone that conveys afferent input from the periphery to the brain regarding the status of body energy stored in the form of fat (reviewed in refs. 1, 2, 3).The weight-reducing action of leptin involves both the inhibition of Agrp neurons (which coexpress the potent orexigen neuropeptide Y) and the stimulation of anorexigenic POMC neurons. Conversely, deficient leptin signaling in ob/ob or db/db mice activates Agrp neurons while inhibiting POMC neurons, a combination that increases food intake and reduces energy expenditure, causing profound obesity. At least 1 downstream component of leptin receptor activation involves phosphorylation of the transcription factor Stat3, and genetic manipulations that interfere with this process cause obesity (4-6), although the relative importance of Stat3 activation in different neuronal subtypes has not been addressed. Previous studies of hypothalamic circuitry and energy balance have focused on changes in membrane potential (7,8), activation of Fos (2), or modulation of synaptic plasticity (9). However, the fundamental question of how leptin activates one cell type but inhibits another remains unanswered.Here we report the development of a molecular genetics strategy that permits dynamic and cell-specific measurement of PI3K activation in hypothalamic POMC or Agrp neurons, using a brain slice

PI3Kα inactivation in leptin receptor cells increases leptin sensitivity but disrupts growth and reproduction

“…Deletion of both subunits disrupts the acute effects of leptin and insulin in resting membrane potential of hypothalamic LR neurons (6,17). However, the physiological consequences of this manipulation have not been determined.…”

“…Phosphatidylinositol 3-kinase (PI3K) signaling is the major molecular pathway associated with these diseases and comorbidities (1)(2)(3). It plays a key role in the central actions of metabolic cues and growth factors in energy balance, glucose homeostasis, and cellular growth (4)(5)(6)(7)(8). Among the multiple PI3K isoforms, those pertaining to class IA are responsive to metabolic signals (9).…”

Modulation of AgRP-neuronal function by SOCS3 as an initiating event in diet-induced hypothalamic leptin resistance

“…We set out to investigate the metabolic phenotypes mediated by SOCS3 up-regulation in AgRP neurons. Mice carrying a Cre-activatable allele of wild-type Socs3 (6) were crossed with mice expressing Cre recombinase specifically in the AgRP neurons (24), such that SOCS3 would be overexpressed specifically in the AgRP neurons. We have previously shown that SOCS3 expression is Cre-dependent, and its expression is upregulated approximately twofold in Cre-expressing cells upon recombination (6).…”

Membrane-initiated estrogen signaling in hypothalamic neurons

“…Both leptin and insulin activate PI3Kinase (via insulin receptor substrate) that leads to the metabolism of phosphatidylinositol (4.5) biphosphate (PIP 2 ) to phoshatidylinositol (3,4,5)-triphosphate (PIP 3 ) in POMC neurons (Xu et al, 2005). Activation of GIRK channels requires permissive levels of membrane PIP 2 and increased channel activity results from Gβγ-mediated stabilization of PIP 2 -GIRK binding (Huang et al, 1998, Zhang et al, 1999.…”