Nutritive, Post-ingestive Signals Are the Primary Regulators of AgRP Neuron Activity

Su, Zhenwei; Alhadeff, Amber L.; Betley, J. Nicholas

doi:10.1016/j.celrep.2017.11.036

Cited by 168 publications

(246 citation statements)

References 56 publications

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“…Prior functional MRI studies, limited to extra-hypothalamic structures, have examined the effect of feeding and of the peripheral administration of metabolically active molecules on appetite and brain activation in healthy volunteers [51,52], and of the neural responses to the passive viewing of food [53][54][55] or food choice in AN [56]. Our results raise the provocative idea that the origin of the disconnect between the body's needs and behavioral choices in patients with AN could lie in the hypothalamus, the metabolic window to the brain, which could fail to accurately sense circulating metabolic signals [57,58] and post-ingestive cues [59,60], and thus relay erroneous information to higher decision centers. The recent correlation of genetic variants, including some expressed in the hypothalamus, with metabolic traits in AN [5,6], provides further corroboration for this hypothesis.…”

Section: The Arcuate Nucleus and Lha Show Inverse Malwiring In Anmentioning

confidence: 82%

Hypothalamic Structural and Functional Imbalances in Anorexia Nervosa

Florent¹,

Baroncini²,

Jissendi-Tchofo³

et al. 2019

Neuroendocrinology

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The hypothalamus contains integrative systems that support life, including physiological processes such as food intake, energy expenditure, and reproduction. Here, we show that anorexia nervosa (AN) patients, contrary to normal weight and constitutionally lean individuals, respond with a paradoxical reduction in hypothalamic levels of glutamate/ glutamine (Glx) upon feeding. This reversal of the Glx response is associated with decreased wiring in the arcuate nucleus and increased connectivity in the lateral hypothalamic area, which are involved in the regulation on a variety of physiological and behavioral functions including the con-trol of food intake and energy balance. The identification of distinct hypothalamic neurochemical dysfunctions and associated structural variations in AN paves the way for the development of new diagnostic and treatment strategies in conditions associated with abnormal body mass index and a maladaptive response to negative energy balance.

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Section: The Arcuate Nucleus and Lha Show Inverse Malwiring In Anmentioning

confidence: 82%

Hypothalamic Structural and Functional Imbalances in Anorexia Nervosa

Florent¹,

Baroncini²,

Jissendi-Tchofo³

et al. 2019

Neuroendocrinology

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“…As early as 1952, it was known that animals prefer the side of a T-maze if rewarded by nutrients delivered directly into the stomach. 1 Although the responses depend on the nutrient’s caloric value, 7,8,11 how this value is signaled by the gut epithelium to drive preference is unknown. Of all macronutrients, sugars and available analogs have the most defined sensory properties.…”

Section: Main Textmentioning

confidence: 99%

“…Adult C57BL/6J wild-type mice were surgically implanted with catheters into the duodenum with a similar procedure as previously described. 4,52 Mice were anesthetized with isoflurane (1-3% in oxygen). A 2 cm incision was made from the xiphoid process diagonally to the left-mid clavicular line.…”

Section: Duodenal Catheter Surgerymentioning

confidence: 99%

A gut sensor for sugar preference

Sahasrabudhe

et al. 2020

Preprint

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Animals innately prefer caloric sugars over non-caloric sweeteners. Such preference depends on the sugar entering the intestine. [1][2][3][4] Although the brain is aware of the stimulus within seconds, [5][6][7][8] how the gut discerns the caloric sugar to guide choice is unknown. Recently, we discovered an intestinal transducer, known as the neuropod cell. 9,10 This cell synapses with the vagus to inform the brain about glucose in the gut in milliseconds. 10 Here, we demonstrate that neuropod cells distinguish a caloric sugar from a non-caloric sweetener using the electrogenic sodium glucose co-transporter 1 (SGLT1) or sweet taste receptors. Activation of neuropod cells by non-caloric sucralose leads to ATP release, whereas the entry of caloric sucrose via SGLT1 stimulates glutamate release. To interrogate the contribution of the neuropod cell to sugar preference, we developed a method to record animal preferences in real time while using optogenetics to silence or excite neuropod cells. We discovered that silencing these cells, or blocking their glutamatergic signaling, renders the animals unable to recognize the caloric sugar. And, exciting neuropod cells leads the animal to consume the non-caloric sweetener as if it were caloric. By transducing the precise identity of the stimuli entering the gut, neuropod cells guide an animal's internal preference toward the caloric sugar. Main TextThe cephalic senses guide our decision to eat. But what happens next, inside the gut, is essential for our eating preferences.As early as 1952, it was known that animals prefer the side of a T-maze if rewarded by nutrients delivered directly into the stomach. 1 Although the responses depend on the nutrient's caloric value, 7,8,11 how this value is signaled by the gut epithelium to drive preference is unknown. Of all macronutrients, sugars and available analogs have the most defined sensory properties. For instance, sucrose -a compound sugar made of D-glucose and fructose-contains both taste and calorie, whereas non-caloric sweeteners, like sucralose, carry only taste. Animals have an innate preference for sucrose over non-caloric sweeteners, even in the absence of taste. 3,12-14 Such preference depends on the sugar entering the intestine. 2,3,15,16 But slow acting intestinal hormones cannot account for the effect, 17 because the brain perceives stimuli from nutrients entering the small intestine within seconds. 6,8,10 Thus, a fast intestinal sensor must exist to steer the animal towards the caloric sugar.A gut sense for sweets. Intestinal signals arising from the lumen are relayed to the brain via the vagus nerve. 6,10,11 The vagus responds within seconds to an intraluminal stimulus of sucrose, 6,10,18 but the response to other sugars, including non-caloric sweeteners, is unclear. We therefore tested vagal firing responses to a panel of sugars: sucrose, D-glucose, fructose, galactose, maltodextrin, alpha-methylglucopyranoside (α-mgp), saccharin, acesulfame-K, and sucralose. All stimuli were perfused at physiological concentrati...

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“…In both cases, the NTS outputs interrupts food ingestion, and until recently had not been implicated in the regulation of hunger, the long-term control of satiety, or hedonic feeding. Studies applying molecular genetics or modern circuit analysis tools to the functional characterization of NTS neurons revealed that the NTS can in fact modulate a much bigger range of behavioral effectors of energy balance including meal initiation and satiety (Blouet & Schwartz, 2012; D’Agostino et al, 2016; Gaykema et al, 2017; Hayes et al, 2011; Su et al, 2017). Yet, little is known about the neural mechanisms through which the NTS regulates forebrain hunger and satiety circuits, and the physiological contexts in which these NTS feeding-regulatory forebrain-projecting outputs are engaged.…”

Section: Introductionmentioning

confidence: 99%

Nutrient sensing in the nucleus of the solitary tract mediates non-aversive suppression of feeding via inhibition of AgRP neurons

Tsang

Nuzacci

Darwish

et al. 2020

Preprint

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10The nucleus of the solitary tract (NTS) is emerging as a major site of action for the appetite-suppressive 11 effects of leading pharmacotherapies currently investigated for the treatment of obesity. However, our 12 understanding of how NTS neurons regulate appetite remains incomplete. Here we used NTS nutrient 13 sensing as an entry point to characterize stimulus-defined neuronal ensembles engaged by the NTS to 14 produce physiological satiety. Using activity-dependent expression of genetically-encoded circuit 15 analysis tools, we found that NTS detection of leucine engages NTS prolactin-releasing peptide (PrRP) 16 neurons to inhibit AgRP neurons via a population of leptin-receptor-expressing neurons in the 17 dorsomedial hypothalamus. This circuit is necessary for the anorectic response to NTS leucine, the 18 appetite-suppressive effect of high protein diets, and the long-term control of energy balance. These 19 results extends the integrative capability of AgRP neurons to include brainstem nutrient sensing inputs. 21Keywords: nucleus of the solitary tract, appetite, obesity, AgRP neurons, hypothalamus, PrRP neurons, 22 metabolic diseases, circuit mapping 23 24 52 provides a neuroanatomical basis for the latter (Petrov et al., 1993), which could explain the ability of 53 high doses of the satiation hormones like CCK to recruit aversive circuits (Swerdlow et al., 1983), and/or 54 provide a mechanism for the synergistic feeding suppressive effects produced by the combination of 55 anorectic signals (Bhavsar et al., 1998; Blevins et al., 2009; Blouet & Schwartz, 2012). Addressing this 56 3 question with molecularly-defined circuit analysis tools is difficult because most identified NTS 57 neurochemical subsets are functionally heterogeneous, respond to multiple cues and project widely 58 throughout the neuraxis (D'Agostino et al., 2016; Rinaman, 2010). Instead, it may be possible to better 59 understand the functional organization of NTS feeding-regulatory circuits using functionally-defined 60 circuit mapping, which could be particularly insightful if subsets of NTS neurons are specialized in the 61 transmission of highly specific sensory cues and organized in a similar fashion as gustatory and vagal 62 sensory neurons (Bai et al., 2019; Williams et al., 2016). Applying such a strategy to signals able to 63 produce satiation or satiety without negative consequences may lead to important new understanding 64 of how to pharmacologically suppress appetite without undesirable side effects. 65We previously showed that NTS sensing of the branched-chain amino acid leucine not only 66 modulates the control of meal size but also rapidly suppresses hunger in fasted animals and increases 67 satiety without the production of conditioned taste aversion (Blouet & Schwartz, 2010; Cheng et al., 68 2020). Here, we used NTS leucine sensing as a functional entry point to investigate ascending neural 69 circuits engaged by NTS neurons to modulate hunger and satiety. In these experiments, Leucine is 70 injected into the NTS ...

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Nutritive, Post-ingestive Signals Are the Primary Regulators of AgRP Neuron Activity

Cited by 168 publications

References 56 publications

Hypothalamic Structural and Functional Imbalances in Anorexia Nervosa

Hypothalamic Structural and Functional Imbalances in Anorexia Nervosa

A gut sensor for sugar preference

Nutrient sensing in the nucleus of the solitary tract mediates non-aversive suppression of feeding via inhibition of AgRP neurons

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