PNOCARC Neurons Promote Hyperphagia and Obesity upon High-Fat-Diet Feeding

Jais, Alexander; Paeger, Lars; Sotelo-Hitschfeld, Tamara; Bremser, Stephan; Prinzensteiner, Melanie; Klemm, Paul; Mykytiuk, Vasyl; Widdershooven, Pia J.M.; Vesting, Anna Juliane; Grzelka, Katarzyna; Minère, Marielle; Cremer, Anna Lena; Xu, Jie; Korotkova, Tatiana; Lowell, Bradford B.; Zeilhofer, Hanns Ulrich; Backes, Heiko; Fenselau, Henning; Wunderlich, Frank; Kloppenburg, Peter; Brüning, Jens C.

doi:10.1016/j.neuron.2020.03.022

Cited by 74 publications

(79 citation statements)

References 74 publications

(75 reference statements)

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“…NOP receptors are expressed in NPY/AgRP neurons, and N/OFQ increases AgRP release from mediobasal hypothalamic explants [ 180 ]. Interestingly, these ARC N/OFQ neurons co-release GABA upon low-frequency optogenetic stimulation, which can provide additional inhibitory input onto POMC neurons [ 181 ]. They are also regulated by ambient levels of extracellular glucose, and inhibited by leptin [ 181 ].…”

Section: Nociceptin/orphanin Fq Regulation Of Homeostatic and Hedomentioning

confidence: 99%

“…Interestingly, these ARC N/OFQ neurons co-release GABA upon low-frequency optogenetic stimulation, which can provide additional inhibitory input onto POMC neurons [ 181 ]. They are also regulated by ambient levels of extracellular glucose, and inhibited by leptin [ 181 ]. On the other hand, N/OFQ administered into the perifornical/lateral hypothalamic area exerts a hypophagic effect attributed to a NOP receptor-mediated inhibition of orexin neurons via activation of K ATP channels [ 182 ].…”

Section: Nociceptin/orphanin Fq Regulation Of Homeostatic and Hedomentioning

confidence: 99%

“…In addition to sex differences, diet modifications resulting lean or obese phenotypes alter the signaling effects of N/OFQ in homeostatic and hedonic neural circuits, and increases the risk for aberrant feeding-behavioral patterns to form. Diet-induced obesity increases the intrinsic excitability of ARC N/OFQ neurons, which augments the inhibitory GABAergic tone received by POMC neurons [ 181 ]. Conversely, ablation of ARC N/OFQ neurons hinders the development of obesity caused by a four-week exposure to a HFD [ 181 ].…”

Section: Nociceptin/orphanin Fq Regulation Of Homeostatic and Hedomentioning

confidence: 99%

“…Diet-induced obesity increases the intrinsic excitability of ARC N/OFQ neurons, which augments the inhibitory GABAergic tone received by POMC neurons [ 181 ]. Conversely, ablation of ARC N/OFQ neurons hinders the development of obesity caused by a four-week exposure to a HFD [ 181 ]. Moreover, diet-induced obesity renders VMN SF-1/ARC POMC synapses more susceptible to the inhibitory effects of exogenous N/OFQ in males and hypoestrogenic OVX females [ 5 ].…”

Section: Nociceptin/orphanin Fq Regulation Of Homeostatic and Hedomentioning

confidence: 99%

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Adaptive Changes in the Central Control of Energy Homeostasis Occur in Response to Variations in Energy Status

Gastelum

Perez

Hernández

et al. 2021

IJMS

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Energy homeostasis is regulated in coordinate fashion by the brain-gut axis, the homeostatic energy balance circuitry in the hypothalamus and the hedonic energy balance circuitry comprising the mesolimbcortical A10 dopamine pathway. Collectively, these systems convey and integrate information regarding nutrient status and the rewarding properties of ingested food, and formulate it into a behavioral response that attempts to balance fluctuations in consumption and food-seeking behavior. In this review we start with a functional overview of the homeostatic and hedonic energy balance circuitries; identifying the salient neural, hormonal and humoral components involved. We then delve into how the function of these circuits differs in males and females. Finally, we turn our attention to the ever-emerging roles of nociceptin/orphanin FQ (N/OFQ) and pituitary adenylate cyclase-activating polypeptide (PACAP)—two neuropeptides that have garnered increased recognition for their regulatory impact in energy homeostasis—to further probe how the imposed regulation of energy balance circuitry by these peptides is affected by sex and altered under positive (e.g., obesity) and negative (e.g., fasting) energy balance states. It is hoped that this work will impart a newfound appreciation for the intricate regulatory processes that govern energy homeostasis, as well as how recent insights into the N/OFQ and PACAP systems can be leveraged in the treatment of conditions ranging from obesity to anorexia.

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Section: Nociceptin/orphanin Fq Regulation Of Homeostatic and Hedomentioning

confidence: 99%

Section: Nociceptin/orphanin Fq Regulation Of Homeostatic and Hedomentioning

confidence: 99%

Section: Nociceptin/orphanin Fq Regulation Of Homeostatic and Hedomentioning

confidence: 99%

Section: Nociceptin/orphanin Fq Regulation Of Homeostatic and Hedomentioning

confidence: 99%

See 2 more Smart Citations

Adaptive Changes in the Central Control of Energy Homeostasis Occur in Response to Variations in Energy Status

Gastelum

Perez

Hernández

et al. 2021

IJMS

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“…TPH2 is the rate-Differential enrichment of genes after leptin treatment. PhosphoTRAP was performed on the samples indicated below, and the RNA abundance determined by the number of RNA-seq reads was plotted in pair-wise comparisons showing (A) differential enrichment of genes in pS6 immunoprecipitates determined by RNA-seq in14 d leptin treatment of ob/ob mice vs. PBS in (A) hypothalamus and (B) brainstem. TaqMan assays were then performed for the pS6-precipitated polysomes after 14 d PBS treatment of ob/ob mice after leptin treatment (for 2, 4, 7, and 14 d) of ob mice and after 14 d PBS treatment of WT mice.…”

mentioning

confidence: 99%

Restriction of food intake by PPP1R17-expressing neurons in the DMH

Çağlar

Friedman

2021

Proc. Natl. Acad. Sci. U.S.A.

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Leptin-deficient ob/ob mice eat voraciously, and their food intake is markedly reduced by leptin treatment. In order to identify potentially novel sites of leptin action, we used PhosphoTRAP to molecularly profile leptin-responsive neurons in the hypothalamus and brainstem. In addition to identifying several known leptin responsive populations, we found that neurons in the dorsomedial hypothalamus (DMH) of ob/ob mice expressing protein phosphatase 1 regulatory subunit 17 (PPP1R17) constitutively express cFos and that this is suppressed by leptin treatment. Because ob mice are hyperphagic, we hypothesized that activating PPP1R17 neurons would increase food intake. However, chemogenetic activation of PPP1R17 neurons decreased food intake and body weight of ob/ob mice while inhibition of PPP1R17 neurons increased them. Similarly, in a scheduled feeding protocol that elicits increased consumption, mice also ate more when PPP1R17 neurons were inhibited and ate less when they were activated. Finally, we found that pair-feeding of ob mice reduced cFos expression to a similar extent as leptin and that reducing the amount of food available during scheduled feeding in DMHPpp1r17 neurons also decreased cFos in DMHPpp1r17 neurons. Finally, these neurons do not express the leptin receptor, suggesting that the effect of leptin on these neurons is indirect and secondary to reduced food intake. In aggregate, these results show that PPP1R17 neurons in the DMH are activated by increased food intake and in turn restrict intake to limit overconsumption, suggesting that they function to constrain binges of eating.

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The Hypothalamic Epigenetic Landscape in Dietary Obesity

Ma,

Yin,

et al. 2023

Advanced Science

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The hypothalamus in the brain plays a pivotal role in controlling energy balance in vertebrates. Nutritional excess through high‐fat diet (HFD) feeding can dysregulate hypothalamic signaling at multiple levels. Yet, it remains largely unknown in what magnitude HFD feeding may impact epigenetics in this brain region. Here, it is shown that HFD feeding can significantly alter hypothalamic epigenetic events, including posttranslational histone modifications, DNA methylation, and chromatin accessibility. The authors comprehensively analyze the chromatin immunoprecipitation‐sequencing (ChIP‐seq), methylated DNA immunoprecipitation‐sequencing (MeDIP‐seq), single nucleus assay for transposase‐accessible chromatin using sequencing (snATAC‐seq), and RNA‐seq data of the hypothalamus of C57 BL/6 mice fed with a chow or HFD for 1 to 6 months. The chromatins are categorized into 6 states using the obtained ChIP‐seq data for H3K4me3, H3K27ac, H3K9me3, H3K27me3, and H3K36me3. A 1‐month HFD feeding dysregulates histone modifications and DNA methylation more pronouncedly than that of 3‐ or 6‐month. Besides, HFD feeding differentially impacts chromatin accessibility in hypothalamic cells. Thus, the epigenetic landscape is dysregulated in the hypothalamus of dietary obesity mice.

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PNOCARC Neurons Promote Hyperphagia and Obesity upon High-Fat-Diet Feeding

Abstract: Highlights d Acute high-fat-diet feeding activates PNOC neurons in the arcuate nucleus (ARC) d GABAergic PNOC ARC neurons inhibit anorexigenic POMC neurons d Optogenetic activation of PNOC ARC neurons promotes feeding d Ablation of PNOC ARC neurons protects from obesity

Cited by 74 publications

References 74 publications

Adaptive Changes in the Central Control of Energy Homeostasis Occur in Response to Variations in Energy Status

Adaptive Changes in the Central Control of Energy Homeostasis Occur in Response to Variations in Energy Status

Restriction of food intake by PPP1R17-expressing neurons in the DMH

The Hypothalamic Epigenetic Landscape in Dietary Obesity

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