Abstract
Molecular and cellular processes in neurons are critical for sensing and responding to energy deficit states, such as during weight-loss. Agouti related protein (AGRP)-expressing neurons are a key hypothalamic population that is activated during energy deficit and increases appetite and weight-gain. Cell type-specific transcriptomics can be used to identify pathways that counteract weight-loss, and here we report high-quality gene expression profiles of AGRP neurons from well-fed and food-deprived young adult mice. For comparison, we also analyzed Proopiomelanocortin (POMC)-expressing neurons, an intermingled population that suppresses appetite and body weight. We find that AGRP neurons are considerably more sensitive to energy deficit than POMC neurons. Furthermore, we identify cell type-specific pathways involving endoplasmic reticulum-stress, circadian signaling, ion channels, neuropeptides, and receptors. Combined with methods to validate and manipulate these pathways, this resource greatly expands molecular insight into neuronal regulation of body weight, and may be useful for devising therapeutic strategies for obesity and eating disorders.
Highlights
Neurons that express Agouti related protein (Agrp) and Proopiomelanocortin (Pomc) comprise two intermingled molecularly defined populations in the hypothalamic arcuate nucleus (ARC) that mediate whole-body energy homeostasis in conjunction with other cell types
Agouti related protein (AGRP) and POMC neurons were dissociated and manually sorted from the hypothalamic ARC of NpyhrGFP and PomctopazFP transgenic mice, respectively, where the neurons could be identified by fluorescent protein expression (Figure 1A)
Most (94.9%) ARCNPY neurons are reported to express Agrp, which is selectively expressed in this brain area (Broberger et al, 1998), we refer to these cells as AGRP neurons
Summary
Neurons that express Agouti related protein (Agrp) and Proopiomelanocortin (Pomc) comprise two intermingled molecularly defined populations in the hypothalamic arcuate nucleus (ARC) that mediate whole-body energy homeostasis in conjunction with other cell types. Weight loss is accompanied by increased Agrp and Npy gene co-expression in AGRP neurons (Hahn et al, 1998), as well as increased electrical activity (Takahashi and Cone, 2005) and synaptic plasticity (Yang et al, 2011; Liu et al, 2012). During energy deficit, POMC neurons decrease electrical activity due to inhibitory synaptic input from AGRP neurons (Takahashi and Cone, 2005; Atasoy et al, 2012), and Pomc neuropeptide gene expression is reduced (Schwartz et al, 1997). AGRP and POMC neurons are both associated with sensing and counteracting energy deficit states Because these neurons play major reciprocal roles in energy homeostasis, investigations of the molecular response pathways for AGRP and POMC neurons to weight-loss are critical for identifying key control points associated with regulation of body weight
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