Obesity Induces Hypothalamic Endoplasmic Reticulum Stress and Impairs Proopiomelanocortin (POMC) Post-translational Processing

Çakır, Işın; Cyr, Nicole E.; Perelló, Mario; Litvinov, Bogdan Patedakis; Romero, Amparo; Stuart, Ronald C.; Nillni, Eduardo A.

doi:10.1074/jbc.m113.475343

Cited by 93 publications

(103 citation statements)

References 70 publications

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“…Both the 48-h and 2-wk HFD-treated groups also exhibited trends for decreased levels of all POMC peptides, with the decrease in ACTH after the 48-h HFD (P Ͻ 0.05) and ␤-endorphin levels after chronic HFD (P Ͻ 0.05) reaching significance. Neither acute nor 2 wk leptin treatments significantly modified the individual POMC peptide levels, but there were slight changes in the molar ratio of ACTH/␣-MSH consistent with alterations in POMC peptide processing (8,50).…”

Section: E909 Leptin-independent Diet Effects On Pomc Peptidesmentioning

confidence: 83%

“…By contrast, a surplus of calories from fat or an exogenous injection of the fat-derived adipokine leptin have been reported to increase transcription of Pomc and the synthesis of POMC peptides (25,34,45,50,62,70). However, extended bouts of high-fat diet (HFD) are also reported to diminish the expression of POMC peptides and the conversion of ACTH to ␣-MSH (8,17,39,63). Likewise, diet-dependent changes in POMC peptide levels are also conferred, at least in part, by tandem regulation of peptide cleavage and peptide-modifying enzymes (8,25,46).…”

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confidence: 97%

“…However, extended bouts of high-fat diet (HFD) are also reported to diminish the expression of POMC peptides and the conversion of ACTH to ␣-MSH (8,17,39,63). Likewise, diet-dependent changes in POMC peptide levels are also conferred, at least in part, by tandem regulation of peptide cleavage and peptide-modifying enzymes (8,25,46).Problematically, there is a lack of consensus regarding POMC peptide levels in POMC neurons under different dietary conditions due to the use of different animal models (species, sex, and age), time points, stimuli, and experimental assays (63). To address these issues, we established acute (24 -48 h) and chronic (2 wk) diet manipulations utilizing food restriction, HFD, or leptin treatment with 8-to 10-wk-old male C57BL/6 POMC-Discosoma red fluorescent protein (DsRed) transgenic reporter mice and assessed the changes in nutritional state on POMC peptide levels in the hypothalamus.…”

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confidence: 99%

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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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Section: E909 Leptin-independent Diet Effects On Pomc Peptidesmentioning

confidence: 83%

mentioning

confidence: 97%

mentioning

confidence: 99%

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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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“…Corroborating this theory, preclinical studies found that specific overexpression of molecular ER components can prevent dietary inhibition of leptin signalling [22]. Accordingly, pharmacological application of the chemical chaperones tauroursodeoxycholic acid (TUDCA) and 4-phenyl butyric acid (4-PBA) can alleviate hypothalamic ER stress to reverse diet-induced leptin resistance [22][23][24]. These chemical chaperones stabilise protein folding by decreasing the formation of abnormal protein aggregates, which reduces ER stress.…”

Section: Targeting Leptin Responsiveness With Pharmacologymentioning

confidence: 99%

“…An imbalance between the loading and folding capacities of the ER results in a condition known as ER stress. Pioneering studies have demonstrated a causal link between hypothalamic ER stress, leptin signalling and obesity [22,23] (Fig. 1).…”

Section: Targeting Leptin Responsiveness With Pharmacologymentioning

confidence: 99%

Renaissance of leptin for obesity therapy

et al. 2016

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Diet-induced obesity and its metabolic comorbidities constitute an overwhelming health crisis and there is an urgent need for safe and effective pharmacological interventions. Being largely shelved for decades, scientists are now revisiting the antiobesity virtues of leptin. Whereas it remains evident that leptin as a stand-alone therapy is not an effective approach, the potential for employing sensitising pharmacology to unleash the weight-lowering properties of leptin has injected new hope into the field. Fascinatingly, these leptin-sensitising agents seem to act via distinct metabolic pathways and may thus, in parallel with their clinical development, serve as important research tools to progress our understanding of the molecular, physiological and behavioural pathways underlying energy homeostasis and obesity pathophysiology. This review summarises a presentation given at the 'Is leptin coming back?' symposium at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium

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Modulation of leptin resistance by food compounds

Aragonès

Ardid-Ruiz

Ibars

et al. 2016

Molecular Nutrition Food Res

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Leptin is mainly secreted by white adipose tissue and regulates energy homeostasis by inhibiting food intake and stimulating energy expenditure through its action in neuronal circuits in the brain, particularly in the hypothalamus. However, hyperleptinemia coexists with the loss of responsiveness to leptin in common obese conditions. This phenomenon has been defined as leptin resistance and the restoration of leptin sensitivity is considered to be a useful strategy to treat obesity. This review summarizes the existing literature on potentially valuable nutrients and food components to reverse leptin resistance. Notably, several food compounds, such as teasaponins, resveratrol, celastrol, caffeine, and taurine among others, are able to restore the leptin signaling in neurons by overexpressing anorexigenic peptides (proopiomelanocortin) and/or repressing orexigenic peptides (neuropeptide Y/agouti-related peptide), thus decreasing food intake. Additionally, some nutrients, such as vitamins A and D, can improve leptin transport through the blood-brain barrier. Therefore, food components can improve leptin resistance by acting at different levels of the leptin pathway; moreover, some compounds are able to target more than one feature of leptin resistance. However, systematic studies are necessary to define the actual effectiveness of each compound.

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Obesity Induces Hypothalamic Endoplasmic Reticulum Stress and Impairs Proopiomelanocortin (POMC) Post-translational Processing

Cited by 93 publications

References 70 publications

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

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

Renaissance of leptin for obesity therapy

Modulation of leptin resistance by food compounds

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