Abstract
Understanding the neural components modulating feeding-related behavior and energy expenditure is crucial to combating obesity and its comorbidities. Neurons within the paraventricular nucleus of the hypothalamus (PVH) are a key component of the satiety response; activation of the PVH decreases feeding and increases energy expenditure, thereby promoting negative energy balance. In contrast, PVH ablation or silencing in both rodents and humans leads to substantial obesity. Recent studies have identified genetically-defined PVH subpopulations that control discrete aspects of energy balance (e.g. oxytocin (OXT), neuronal nitric oxide synthase 1 (NOS1), melanocortin 4-receptor (MC4R), prodynorphin (PDYN)). We previously demonstrated that non-OXT NOS1PVH neurons contribute to PVH-mediated feeding suppression. Here, we identify and characterize a non-OXT, non-NOS1 subpopulation of PVH and peri-PVH neurons expressing insulin-receptor substrate 4 (IRS4PVH) involved in energy balance control. Using Cre-dependent viral tools to activate, trace and silence these neurons, we highlight the sufficiency and necessity of IRS4PVH neurons in normal feeding and energy expenditure regulation. Furthermore, we demonstrate that IRS4PVH neurons lie within a complex hypothalamic circuitry that engages distinct hindbrain regions and is innervated by discrete upstream hypothalamic sites. Overall, we reveal a requisite role for IRS4PVH neurons in PVH-mediated energy balance which raises the possibility of developing novel approaches targeting IRS4PVH neurons for anti-obesity therapies.
Highlights
Genetic polymorphisms associated with obesity are disproportionately clustered in pathways affecting neural function and architecture in the central nervous system (CNS)[1]
Since in situ hybridization (Allen Mouse Brain Atlas13) reveals dense Irs[4] expression in and adjacent to the paraventricular nucleus of the hypothalamus (PVH), we sought to determine the role of IRS4PVH neurons in energy homeostasis using Cre-dependent technologies in combination with a novel insulin receptor substrate-4 (IRS4)-iCre knock-in mouse model in which Cre recombinase expression is tethered to Irs[4] (Fig. 1A)
To determine if IRS4PVH neurons are contained within the NOS1PVH population, we stained brain slices from IRS4-iCre mice injected with AAV-Flex-GFP for NOS1 peptide and GFP and found that IRS4PVH neurons are a separate population from NOS1PVH cells (Fig. 1E)
Summary
Genetic polymorphisms associated with obesity are disproportionately clustered in pathways affecting neural function and architecture in the central nervous system (CNS)[1]. Manipulation of other PVH populations, such as neuronal nitric oxide synthase 1 (NOS1PVH) neurons, is sufficient to alter both feeding and energy expenditure[10] This raises the possibility that distinct PVH cell types might independently or coordinately regulate feeding and/or energy expenditure. We discovered that Irs[4] is expressed in and adjacent to the PVH and that the paraventricular and periventricular IRS4-expressing cell population (referred to as IRS4PVH) is both necessary and sufficient for normal feeding and bodyweight, suggesting a functional role for PVH and peri-PVH Irs4-expressing neurons in the control of energy homeostasis. Our study proposes a novel framework for the regulation of bodyweight consisting of multiple interconnected PVH populations that are potentially under independent control to modulate distinct energy balance parameters including feeding and energy expenditure
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