Coexpression of Agrp and NPY in fasting-activated hypothalamic neurons

Abstract

predicted that the POMC gene should be expressed in ARC neurons that do not contain Agrp mRNA. To determine if NPY mRNA is coexpressed with either Agrp or POMC mRNA in ARC neurons of fed and fasted mice and rats, we colocalized nature neuroscience • volume 1 no 4 • Neuropeptide Y (NPY) stimulates food intake and promotes weight gain, whereas melanocortins have the opposite effect. Yet both peptides are synthesized in the arcuate nucleus, a hypothalamic area involved in energy homeostasis. We report here that mRNA encoding NPY and the melanocortin precursor, proopiomelanocortin (POMC) are expressed in adjacent, but distinct, subpopulations of arcuate nucleus neurons. Moreover, these NPY neurons coexpress mRNA encoding Agouti-related protein (Agrp), an endogenous melanocortin receptor antagonist, and fasting increases the expression of both of these mRNA species. Our findings suggest that hypothalamic NPY/Agrp neurons constitute a unique cell type that is activated by fasting to stimulate food intake via a simultaneous increase of NPY and decrease of melanocortin.The ability to recover weight lost during periods of limited access to food is important for survival. Accordingly, a highly integrated central nervous system response to starvation and weight loss has evolved that includes changes in the activity of discrete hypothalamic pathways involved in energy homeostasis 1,2 . Components of this response include the activation of hypothalamic neurons that contain NPY (which stimulates food intake) coupled with reduced signaling by neurons that contain melanocortins (which inhibit food intake). Melanocortin-containing cell bodies in the forebrain have been detected only in the hypothalamic arcuate nucleus (ARC), the same nucleus that contains a population of NPY neurons that are implicated as critical in energy homeostasis 3 . Similarly, hypothalamic expression of Agrp 4,5 (also known as Agouti-related transcript, ART), a newly discovered antagonist of melanocortin receptors, has also been found only in neurons of the ARC.These anatomical considerations, as well as the ability of NPY and Agrp to promote increased food intake and weight gain 1,4 , led us to propose that these two gene products are expressed by the same ARC neurons, as proposed previously 5 . We hypothesized further that if NPY and Agrp are coexpressed by ARC neurons, their expression should be regulated in parallel during fasting. In contrast, because melanocortins reduce food intake 6 , we Fig. 1. Fluorescent in situ hybridization of mRNA encoding Agrp in the ARC of mice fed ad libitum (a) or fasted (b). Adult male mice (25 g) were fasted for 48 h. Brains were removed after decapitation, frozen on dry ice and sectioned at 14 µm. In situ hybridization used antisense Agrp cRNA probe. Sections were viewed with a Zeis Axioplan fluorescence microscope and quantified using MCID M2 imaging software (Imaging Research, Ontario, Canada). The expression of Agrp mRNA increases with fasting. All animals were treated in accordance with University of Washington gui...

Abnormalities of the somatotrophic axis in the obese agouti mouse

“…40 However, Kesterson and colleagues appear to have studied Arc NPY expression in more posterior coronal sections, which may explain the discrepancy in results. Since the majority of Arc AgRP neurones coexpress NPY, 41,42 the demonstration of a reduction in Arc AgRP mRNA expression in obese A y /a mice 43 supports our observations. In addition, NPY may suppress the somatotrophic axis via stimulation of hypothalamic somatostatin release.…”

Body weight is regulated by the brain: a link between feeding and emotion

“…93,94 In contrast to POMC mRNA, AgRP mRNA is increased in leptindeficient ob/ob mice and leptin-resistant db/db mice, and during periods of fasting when leptin levels rapidly fall. 97,98 Finally, it is important to note that AgRP is coexpressed with NPY in the Arc (see the section 'the NPY/Y1-receptor system'). 71 (also applied to (a)), 200 mm in (d) (also applied to (c)), 100 mm in (f) (also applied to (e)).…”

“…149,150 Importantly, NPY-producing Arc neurons coexpress AgRP and are inhibited by leptin. 66,68,69,97,98 Of NPY receptor subtypes, the Y1-, (Y1-R), Y2-, and Y5-receptors have been implicated in the regulation ), with permission). h: GFP-producing cell labeling the MC4-R. Bar ¼ 10 mm.…”

AMP-activated protein kinase in the brain

“…Food deprivation increases and overconsumption decreases NPY and AgRP. [53][54][55] Thus, positive energy balance should activate anorexigenic/catabolic pathways originating in the lateral ARC, and inhibit orexigenic/anabolic pathways from the medial ARC. Negative energy balance would have the opposite effects.…”