Early postnatal amylin treatment enhances hypothalamic leptin signaling and neural development in the selectively bred diet-induced obese rat

Johnson, Miranda D.; Bouret, Sébastien G.; Dunn-Meynell, Ambrose A.; Boyle, Christina N.; Lutz, Thomas; Levin, Barry E.

doi:10.1152/ajpregu.00326.2016

Cited by 24 publications

(36 citation statements)

References 48 publications

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“…Furthermore, c‐Fos expression was found to be regulated by amylin in an MC4R‐dependent manner, and amylin increased MC4R expression, which could be blocked by SHU9119. In this mechanism, amylin may facilitate release of MC4R agonists, which then activate MC4R‐expressing neurons, and SHU9119 may block these effects, resulting in increased MC4R expression.…”

Section: Discussionmentioning

confidence: 99%

Melanocortin 4 receptor–mediated effects of amylin on thermogenesis and regulation of food intake

Fan

et al. 2019

Diabetes Metabolism Res

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Aims: Amylin, a pancreatic hormone cosecreted with insulin, exerts important anorexic and weight-loss effects. Melanocortin 4 receptor (MC4R) signalling plays a critical role in energy homeostasis; however, its role on amylin-dependent regulation of food intake and adaptive thermogenesis of interscapular brown adipose tissue (IBAT) are unclear. In this study, we examined the effects of amylin on food intake and thermogenesis on IBAT via the MC4R pathway in mice. Materials and methods:Acute food consumption and thermogenesis in IBAT were measured in male wild-type (WT) and MC4R-deficient mice following intraperitoneal injection of amylin and SHU9119, an MC3R/4R antagonist, to determine the role of the central melanocortin system on the hypothalamus and IBAT. Results: Amylin (50 μg/kg) suppressed feeding and stimulated thermogenesis on IBAT via activation of the MC4R system in mice. Pharmacological blockade of MC4R using SHU9119 (50 μg/kg) attenuated amylin-induced inhibition of feeding and stimulation of thermogenesis in IBAT. No changes were observed when SHU9119 was injected alone. Moreover, amylin significantly increased MC4R expression and c-Fos neuronal signals in the arcuate nucleus and significantly increased acetyl-CoA carboxylase (ACC) phosphorylation in the hypothalamus and IBAT and uncoupling protein-1 (UCP1) expression in the IBAT of WT mice via the MC4R pathway. Conclusion: The melanocortin system was involved in amylin-induced suppression of food intake and activation of thermogenesis in both the hypothalamus and IBAT via modulation of ACC phosphorylation and UCP1 expression. KEYWORDS amylin, brown adipose tissue, food intake, hypothalamus, melanocortin 4 receptor, thermogenesis 1 | INTRODUCTION Studies of central nervous system (CNS) regulation of body temperature and thermogenesis have revealed that amylin exerts glucoselowering effects, promotes anorexia, and induces weight loss in both humans and rodents. 1,2 Amylin, a 37-amino acid peptide hormone cosecreted with insulin from pancreatic β-cells in response to nutrient ingestion, acts as a signal of satiation and adiposity, and circulating levels of amylin are higher in obese individuals than in normal-weight individuals. 3 These effects are triggered via amylin receptors in the area postrema (AP), and subsequent activation involves the solitary tract, lateral parabrachial nucleus, and other brain areas. 4Xiaojing Li and Kuikui Fan contributed equally to this work.

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Section: Discussionmentioning

confidence: 99%

Melanocortin 4 receptor–mediated effects of amylin on thermogenesis and regulation of food intake

Fan

et al. 2019

Diabetes Metabolism Res

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“…Singlelabel p-ERK IHC was carried out as previously described using rabbit anti-p-ERK antibody (1:1,000) (27,37). Doublelabeled p-ERK-POMC IHC was carried out subsequently (22) by incubating sections for 72 h with rabbit anti-POMC antibody (1:1,000, category no. H-029-30; Phoenix Pharmaceuticals, Karlsruhe, Germany) and Alexa Fluor 488 goat anti-rabbit for 2 h (1:250; Life Technologies) and coverslipped using VECTASHIELD HardSet mounting medium (Vectorlabs, Servion, Switzerland).…”

Section: P-erk and Pomc Ihcmentioning

confidence: 99%

“…aMSH and AgRP IHC aMSH and AgRP IHC were performed using previously described methods (21,22,38). Brains were sectioned at 25 mm serially through the PVN and dorsomedial nucleus (DMN).…”

Section: P-erk and Pomc Ihcmentioning

confidence: 99%

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Amylin Selectively Signals Onto POMC Neurons in the Arcuate Nucleus of the Hypothalamus

et al. 2018

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Amylin phosphorylates ERK (p-ERK) in the area postrema to reduce eating and synergizes with leptin to phosphorylate STAT3 in the arcuate (ARC) and ventromedial (VMN) hypothalamic nuclei to reduce food intake and body weight. The current studies assessed potential amylin and amylin-leptin ARC/VMN interactions on ERK signaling and their roles in postnatal hypothalamic pathway development. In amylin knockout mice, the density of agouti-related protein (AgRP)-immunoreactive (IR) fibers in the hypothalamic paraventricular nucleus (PVN) was increased, while the density of α-melanocyte-stimulating hormone (αMSH) fibers was decreased. In mice deficient of the amylin receptor components RAMP1/3, both AgRP and αMSH-IR fiber densities were decreased, while only αMSH-IR fiber density was decreased in rats injected neonatally in the ARC/VMN with an adeno-associated virus short hairpin RNA against the amylin core receptor. Amylin induced p-ERK in ARC neurons, 60% of which was present in POMC-expressing neurons, with none in NPY neurons. An amylin-leptin interaction was shown by an additive effect on ARC ERK signaling in neonatal rats and a 44% decrease in amylin-induced p-ERK in the ARC of leptin receptor-deficient and of ob/ob mice. Together, these results suggest that amylin directly acts, through a p-ERK-mediated process, on POMC neurons to enhance ARC-PVN αMSH pathway development.

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“…These studies were subsequently carried forward by Judith Gorski, PhD [51–53] and Christa M. Patterson, PhD [53–56], graduate students in lab. They also led to my long-time, fruitful collaborations with Sebastien B. Bouret, PhD in our studies of how genes and the maternal and postnatal environment interact to influence development of hypothalamic pathways, leptin and amylin signaling [53, 56–60]. …”

Section: Introductionmentioning

confidence: 99%

10 lessons learned by a misguided physician

Levin

2017

Physiology & Behavior

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It was a great and humbling honor to receive the 2016 Distinguished Career Award from my SSIB colleagues. This paper summarizes the major points of my DCA talk at the 2016 annual meeting. It is a reflection on my 50 year medical and research career and 10 lessons I have learned over those years which might be of help to young investigators near the beginning of their own research careers. These lessons include: the value of being receptive to the opportunities provided you; how clinician-scientists can serve as critical role models for young investigators like me and a history of how my career developed as a result of their influence; the importance of carefully examining your own data, particularly when it doesn’t agree with your preconceived ideas; the critical role that students, postdocs and PhD (and even veterinarian) colleagues can play in developing one’s career; the likelihood that your career path will have many interesting twists and turns determined by changes in your own scientific interests and how rewarding various areas of research focus are to you; the importance of building a close-knit laboratory staff family; the fact that science and romance can mix. Finally, I offer 3 somewhat self-evident free pieces of advice for building and maintaining a rewarding career.

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Early postnatal amylin treatment enhances hypothalamic leptin signaling and neural development in the selectively bred diet-induced obese rat

Cited by 24 publications

References 48 publications

Melanocortin 4 receptor–mediated effects of amylin on thermogenesis and regulation of food intake

Melanocortin 4 receptor–mediated effects of amylin on thermogenesis and regulation of food intake

Amylin Selectively Signals Onto POMC Neurons in the Arcuate Nucleus of the Hypothalamus

10 lessons learned by a misguided physician

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