Sucrose overconsumption impairs AgRP neuron dynamics and promotes palatable food intake

Lorch, Carolyn M.; Hayes, Nikolas W.; Xia, Jessica L.; Fleps, Stefan W.; McMorrow, Hayley E.; Province, Haley S.; Frydman, Joshua A.; Parker, Jones G.; Beutler, Lisa R.

doi:10.1016/j.celrep.2024.113675

Cited by 4 publications

(6 citation statements)

References 57 publications

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“…However, control experiments showed that mice maintained consistent neural responses to repeated intragastric nutrient infusions over one to two weeks in the absence of antibody treatment (Fig. S3), and multiple prior studies have shown consistent nutrient-mediated AgRP neural responses for several weeks in control mice [26][27][28] . In contrast to the dramatic effects of GIPR blockade, pretreatment with the GLP-1R antagonist exendin 9-39 (Ex-9) had no effect on nutrient-mediated AgRP neuron inhibition (Fig.…”

mentioning

confidence: 77%

“…Fiber photometry data were collected and analyzed as previously described 7,26,28 . For photometry appropriate for photometry experiments.…”

Section: Discussionmentioning

confidence: 99%

“…Fiber photometry data were collected and analyzed as previously described 7,26,28 . For photometry traces shown in Figures 1, 2, 4, and S1-S5, ΔF/F (%) refers to the mean ΔF t /F 0 *100.…”

Section: Methodsmentioning

confidence: 99%

“…Here, we have identified a clear role for GIP in gut-brain communication with AgRP neurons in a manner that is consistent with the anorexigenic effects of GIPR agonism. Further studies will be required to define which GIPR-expressing neurons are required to elicit this effect, and how obesity impacts gut-brain axis responsiveness to incretin hormones in vivo [26][27][28] .…”

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confidence: 99%

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Incretin hormones and pharmacomimetics rapidly inhibit AgRP neuron activity to suppress appetite

McMorrow,

Lorch,

Hayes

et al. 2024

Preprint

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Analogs of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) have become mainstays of obesity and diabetes management. However, both the physiologic role of incretin hormones in the control of appetite and the pharmacologic mechanisms by which incretin-mimetic drugs suppress caloric intake remain incompletely understood. Hunger-promoting AgRP-expressing neurons are an important hypothalamic population that regulates food intake. Therefore, we set out to determine how incretins analogs affect their activity in vivo. Using fiber photometry, we observed that both GIP receptor (GIPR) and GLP-1 receptor (GLP-1R) agonism acutely inhibit AgRP neuron activity in fasted mice and reduce the response of AgRP neurons to food. Moreover, optogenetic stimulation of AgRP neurons partially attenuated incretin-induced feeding suppression, suggesting that AgRP neuron inhibition is necessary for the full appetite-suppressing effects of incretin-based therapeutics. Finally, we found that GIP but not GLP-1 is necessary for nutrient-mediated AgRP neuron inhibition, representing a novel physiologic role for GIP in maintaining energy balance. Taken together, these findings reveal neural mechanisms underlying the efficacy of incretin-mimetic obesity therapies. Understanding these drugs′ mechanisms of action is crucial for the development of next-generation obesity pharmacotherapies with an improved therapeutic profile.

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mentioning

confidence: 77%

“…Fiber photometry data were collected and analyzed as previously described 7,26,28 . For photometry appropriate for photometry experiments.…”

Section: Discussionmentioning

confidence: 99%

“…Fiber photometry data were collected and analyzed as previously described 7,26,28 . For photometry traces shown in Figures 1, 2, 4, and S1-S5, ΔF/F (%) refers to the mean ΔF t /F 0 *100.…”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Incretin hormones and pharmacomimetics rapidly inhibit AgRP neuron activity to suppress appetite

McMorrow,

Lorch,

Hayes

et al. 2024

Preprint

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“…Studies have also found that obesity induced by a high-fat diet disrupts the neuronal response of AgRP to nutritional stimuli, exacerbating the consumption of palatable food and weight gain. 42 NPY neurons are the primary regulators of energy storage in the hypothalamus, and under obese conditions, appetite is mainly driven by NPY produced by this small population of neurons. 43 In our study, intervention with KGM and DKGM was found to be significantly downregulated AgRP, NPY, and ORX gene expression that promotes appetite of high-fat diet-fed mice while significantly upregulating the expression of the POMC gene that inhibits appetite (Figure 6A−C).…”

Section: Effect Of Kgm and Degradationmentioning

confidence: 99%

Effects of KGM and Degradation Products on Appetite Regulation and Energy Expenditure in High-Fat-Diet Mice via the Adipocyte–Hypothalamus Axis

Jin,

Yao,

Wang

et al. 2024

J. Agric. Food Chem.

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Konjac glucomannan (KGM), high-viscosity dietary fiber, is utilized in weight management. Previous investigations on the appetite-suppressing effects of KGM have centered on intestinal responses to nutrients and gastric emptying rates, with less focus on downstream hypothalamic neurons of satiety hormones. In our studies, the molecular mechanisms through which KGM and its degradation products influence energy homeostasis via the adipocyte−hypothalamic axis have been examined. It was found that high-viscosity KGM more effectively stimulates enteroendocrine cells to release glucagon-like peptide-1 (GLP-1) and reduces ghrelin production, thereby activating hypothalamic neurons and moderating short-term satiety. Conversely, low-viscosity DKGM has been shown to exhibit stronger anti-inflammatory properties in the hypothalamus, enhancing hormone sensitivity and lowering the satiety threshold. Notably, both KGM and DKGM significantly reduced leptin signaling and fatty acid signaling in adipose tissue and activated brown adipose tissue thermogenesis to suppress pro-opiomelanocortin (POMC) expression and activate agouti-related protein (AgRP) expression, thereby reducing food intake and increasing energy expenditure. Additionally, high-viscosity KGM has been found to activate the adipocyte−hypothalamus axis more effectively than DKGM, thereby promoting greater daily energy expenditure. These findings provide novel insights into the adipocyte−hypothalamic axis for KGM to suppress appetite and reduce weight.

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Acute elevated dietary fat alone is not sufficient to decrease AgRP projections in the paraventricular nucleus of the hypothalamus in mice

Yagoub,

Chesters,

Ott

et al. 2024

Sci Rep

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Within the brain, the connections between neurons are constantly changing in response to environmental stimuli. A prime environmental regulator of neuronal activity is diet, and previous work has highlighted changes in hypothalamic connections in response to diets high in dietary fat and elevated sucrose. We sought to determine if the change in hypothalamic neuronal connections was driven primarily by an elevation in dietary fat alone. Analysis was performed in both male and female animals. We measured Agouti-related peptide (AgRP) neuropeptide and Synaptophysin markers in the paraventricular nucleus of the hypothalamus (PVH) in response to an acute 48 h high fat diet challenge. Using two image analysis methods described in previous studies, an effect of a high fat diet on AgRP neuronal projections in the PVH of male or female mice was not identified. These results suggest that it may not be dietary fat alone that is responsible for the previously published alterations in hypothalamic connections. Future work should focus on deciphering the role of individual macronutrients on neuroanatomical and functional changes.

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Sucrose overconsumption impairs AgRP neuron dynamics and promotes palatable food intake

Cited by 4 publications

References 57 publications

Incretin hormones and pharmacomimetics rapidly inhibit AgRP neuron activity to suppress appetite

Incretin hormones and pharmacomimetics rapidly inhibit AgRP neuron activity to suppress appetite

Effects of KGM and Degradation Products on Appetite Regulation and Energy Expenditure in High-Fat-Diet Mice via the Adipocyte–Hypothalamus Axis

Acute elevated dietary fat alone is not sufficient to decrease AgRP projections in the paraventricular nucleus of the hypothalamus in mice

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