Food Intake Adaptation to Dietary Fat Involves PSA-Dependent Rewiring of the Arcuate Melanocortin System in Mice

Bénani, Alexandre; Hryhorczuk, Cécile; Gouazé, Alexandra; Fioramonti, Xavier; Brénachot, Xavier; Guissard, Christophe; Krezymon, Alice; Duparc, Thibaut; Colom, André; Nédélec, Emmanuelle; Rigault, Caroline; Lemoine, Aleth; Gadrey, Jean; Gerardy‐Schahn, Rita; Valet, Philippe; Knauf, Claude; Lorsignol, Anne; Pénicaud, Luc

doi:10.1523/jneurosci.0624-12.2012

Cited by 62 publications

(75 citation statements)

References 46 publications

(64 reference statements)

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“…Dietary fat-induced neuronal remodeling has previously been reported in the hypothalamus (Benani et al 2012) and obesity has been found to have neurodegenerative effects in this nucleus (McNay et al 2012). Microglia activation is involved in neuronal circuit remodeling (Kettenmann et al 2013) and has been found to control HFD-induced hypothalamic inflammation and loss of neuronal function (Valdearcos et al 2014).…”

Section: Discussionmentioning

confidence: 96%

Energy‑dense diet triggers changes in gut microbiota, reorganization of gut‑brain vagal communication and increases body fat accumulation

Vaughn¹,

Cooper²,

Lorenzo³

et al. 2017

Acta Neurobiologiae Experimentalis

127

105

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Obesity is associated with consumption of energy-dense diets and development of systemic inflammation. Gut microbiota play a role in energy harvest and inflammation and can influence the change from lean to obese phenotypes. The nucleus of the solitary tract (NTS) is a brain target for gastrointestinal signals modulating satiety and alterations in gut-brain vagal pathway may promote overeating and obesity. Therefore, we tested the hypothesis that high-fat diet-induced changes in gut microbiota alter vagal gut-brain communication associated with increased body fat accumulation. Sprague-Dawley rats consumed a low energy-dense rodent diet (LFD; 3.1 kcal/g) or high energy-dense diet (HFD, 5.24 kcal/g). Minocycline was used to manipulate gut microbiota composition. 16S Sequencing was used to determine microbiota composition. Immunofluorescence against IB4 and Iba1 was used to determine NTS reorganization and microglia activation. Nodose ganglia from LFD rats were isolated and co-cultured with different bacteria strains to determine neurotoxicity. HFD altered gut microbiota with increases in Firmicutes/Bacteriodetes ratio and in pro-inflammatory Proteobacteria proliferation. HFD triggered reorganization of vagal afferents and microglia activation in the NTS, associated with weight gain. Minocycline-treated HFD rats exhibited microbiota profile comparable to LFD animals. Minocycline suppressed HFD-induced reorganization of vagal afferents and microglia activation in the NTS, and reduced body fat accumulation. Proteobacteria isolated from cecum of HFD rats were toxic to vagal afferent neurons in culture. Our findings show that diet-induced shift in gut microbiome may disrupt vagal gut-brain communication resulting in microglia activation and increased body fat accumulation.

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Section: Discussionmentioning

confidence: 96%

Energy‑dense diet triggers changes in gut microbiota, reorganization of gut‑brain vagal communication and increases body fat accumulation

Vaughn¹,

Cooper²,

Lorenzo³

et al. 2017

Acta Neurobiologiae Experimentalis

127

105

View full text Add to dashboard Cite

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“…Leptin was found to additionally regulate the synaptic organization of orexin neurons in the LHA 95 , and ghrelin was shown to modulate synapse formation in the hippocampus 96 and ventral tegmental area (VTA) 97 . Furthermore, hypercaloric challenges in the form of a HFD was also found to induce synaptic remodelling in the ARC 98,99 . Interestingly, deviations in the synaptic inputs to satiety promoting POMC neurons might contribute to the difference in susceptibility of inbred mouse strains to DIO 98 .…”

Section: Central Fgf1 Effects — Possible Mechanismsmentioning

confidence: 93%

FGF1 — a new weapon to control type 2 diabetes mellitus

et al. 2017

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A hypercaloric diet combined with a sedentary lifestyle is a major risk factor in the development of insulin resistance, type 2 diabetes mellitus (T2DM) and associated co-morbidities. Standard treatment for T2DM begins with lifestyle modification, and includes oral medications and insulin therapy to compensate for progressive β-cell failure. Current pharmaceutical options for T2DM, however, are limited in that they do not maintain stable, durable glucose control without the need for treatment intensification. Furthermore, each medication is associated with adverse effects ranging from hypoglycaemia to weight gain or bone loss. Unexpectedly, FGF1 and its low mitogenic variants have emerged as potentially safe candidates in restoring euglycaemia, without causing overt adverse effects. In particular, a single peripheral injection of FGF1 can lower glucose to normal levels in hours without the risk of hypoglycaemia. Similarly, a single intracerebroventricular injection of FGF1 can induce long-lasting remission of the diabetic phenotype. This Review discusses potential mechanisms by which centrally administered FGF1 improves central glucose-sensing and peripheral glucose uptake in a sustained fashion. Specifically, we explore the potential crosstalk between FGF1 and glucose-sensing neuronal circuits, hypothalamic neural stem cells and synaptic plasticity. Finally, we highlight therapeutic considerations of FGF1 and compare its metabolic actions to FGF15/FGF19 and FGF21.

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“…Consequently, the necessity to drive Pomc and ␣-MSH synthesis becomes less crucial to compensate for the state of positive energy balance as the mice begin to normalize their chow intake, despite the small but statistically significant increase in body weight. Whereas HFD has been studied as a mechanism for modifying POMC peptide content, other reports suggest that HFD induces alterations in synaptic scaffold proteins, as well as changes in the synaptic inputs to POMC neurons (3,45,60). However, the interplay between these mechanisms and POMC peptide synthesis is not clear.…”

Section: E910 Leptin-independent Diet Effects On Pomc Peptidesmentioning

confidence: 99%

Temporal changes in nutritional state affect hypothalamic POMC peptide levels independently of leptin in adult male mice

Mercer

Stuart

Attard

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Mercer AJ, Stuart RC, Attard CA, Otero-Corchon V, Nillni EA, Low MJ. Temporal changes in nutritional state affect hypothalamic POMC peptide levels independently of leptin in adult male mice. Am J Physiol Endocrinol Metab 306: E904 -E915, 2014. First published February 11, 2014 doi:10.1152/ajpendo.00540.2013.-Hypothalamic proopiomelanocortin (POMC) neurons constitute a critical anorexigenic node in the central nervous system (CNS) for maintaining energy balance. These neurons directly affect energy expenditure and feeding behavior by releasing bioactive neuropeptides but are also subject to signals directly related to nutritional state such as the adipokine leptin. To further investigate the interaction of diet and leptin on hypothalamic POMC peptide levels, we exposed 8-to 10-wk-old male POMC-Discosoma red fluorescent protein (DsRed) transgenic reporter mice to either 24 -48 h (acute) or 2 wk (chronic) food restriction, high-fat diet (HFD), or leptin treatment. Using semiquantitative immunofluorescence and radioimmunoassays, we discovered that acute fasting and chronic food restriction decreased the levels of adrenocorticotropic hormone (ACTH), ␣-melanocytestimulating hormone (␣-MSH), and ␤-endorphin in the hypothalamus, together with decreased DsRed fluorescence, compared with control ad libitum-fed mice. Furthermore, acute but not chronic HFD or leptin administration selectively increased ␣-MSH levels in POMC fibers and increased DsRed fluorescence in POMC cell bodies. HFD and leptin treatments comparably increased circulating leptin levels at both time points, suggesting that transcription of Pomc and synthesis of POMC peptide products are not modified in direct relation to the concentration of plasma leptin. Our findings indicate that negative energy balance persistently downregulated POMC peptide levels, and this phenomenon may be partially explained by decreased leptin levels, since these changes were blocked in fasted mice treated with leptin. In contrast, sustained elevation of plasma leptin by HFD or hormone supplementation did not significantly alter POMC peptide levels, indicating that enhanced leptin signaling does not chronically increase Pomc transcription and peptide synthesis. arcuate nucleus; energy homeostasis; hypothalamus; metabolism; neural networks; obesity; proopiomelanocortin neurons; leptin; proopiomelanocortin NEURONS IN THE ARCUATE NUCLEUS of the hypothalamus (ARC) containing the proopiomelanocortin (POMC) gene are central to the maintenance of energy homeostasis. Pomc mRNA in these neurons encodes a 241-amino acid prohormone that is enzymatically processed into multiple bioactive peptides. Proconvertase 1/3 (PC1/3) cleaves POMC into adrenocorticotropic hormone (ACTH) and ␤-lipotrophin, which are further processed by PC2 and carboxypeptidase E (CPE) into ␣-melanocyte-stimulating hormone (␣-MSH) and ␤-endorphin (46, 66). In the central nervous system (CNS), ACTH is relatively inactive, but ␣-MSH acts on melanocortin 4 receptor (MC4R) to potently downregulate appetitive behavior and inc...

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Food Intake Adaptation to Dietary Fat Involves PSA-Dependent Rewiring of the Arcuate Melanocortin System in Mice

Cited by 62 publications

References 46 publications

Energy‑dense diet triggers changes in gut microbiota, reorganization of gut‑brain vagal communication and increases body fat accumulation

Energy‑dense diet triggers changes in gut microbiota, reorganization of gut‑brain vagal communication and increases body fat accumulation

FGF1 — a new weapon to control type 2 diabetes mellitus

Temporal changes in nutritional state affect hypothalamic POMC peptide levels independently of leptin in adult male mice

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