Feeding-induced oleoylethanolamide mobilization is disrupted in the gut of diet-induced obese rodents

Igarashi, Miki; DiPatrizio, Nicholas V.; Narayanaswami, Vidya; Piomelli, Daniele

doi:10.1016/j.bbalip.2015.05.006

Cited by 53 publications

(56 citation statements)

References 45 publications

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“…This relationship showed the strongest association to the satiety component of the appetite score and is consistent with the appetite suppression previously associated with L-EA in rodents [12]. Interestingly, while elevated levels of the reported satiety factor oleoyl ethanolamide [20] were detected in female hemodialysis patients, the association with satiety was weaker (P<0.5) and no correlation with appetite scores was observed.…”

Section: Discussionsupporting

confidence: 85%

Association between plasma endocannabinoids and appetite in hemodialysis patients: A pilot study

Friedman

Kim

Kaiser³

et al. 2016

Nutrition Research

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Uremia-associated anorexia may be related to altered levels of long chain n-6 and n-3 polyunsaturated fatty acid (PUFA) derived circulating endocannabinoids (EC) and EC-like compounds that are known to mediate appetite. Our study's hypothesis was that such molecules are associated with appetite in patients with end-stage renal disease. A cross-sectional observational study was performed in 20 chronic hemodialysis patients (9 females, 11 males) and 10 healthy female controls in whom appetite was assessed using the Simplified Nutritional Appetite Questionnaire (SNAQ) and blood drawn in the fasting (and when applicable) pre-dialysis state. Blood levels of PUFA and EC were also measured. Higher blood levels of the long chain n-6 fatty acid 20:4n6 (arachidonic acid) and lower levels of the long chain n-3 fatty acid 20:5n3 (eicosapentaenoic acid) were observed in female hemodialysis patients compared to controls. No differences were observed between male and female patients. In female study participants strong correlations between specific EC-like compounds and total SNAQ scores were noted, including with the n-6 PUFA derived linoleoyl ethanolamide (L-EA; ρ= -0.60, P<0.01) and the n-3 PUFA derived docosahexaenoyl ethanolamide (DH-EA; ρ= 0.63, P<0.01). The L-EA:DH-EA ratio was most strongly associated with the SNAQ score (ρ= -0.74, P≤0.001), and its questions associated with appetite (ρ= -0.69, P≤0.01) and satiety (ρ= -0.81, P≤0.001). These findings support a link between circulating EC and appetite in hemodialysis patients.

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Section: Discussionsupporting

confidence: 85%

Association between plasma endocannabinoids and appetite in hemodialysis patients: A pilot study

Friedman

Kim

Kaiser³

et al. 2016

Nutrition Research

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“…Food deprivation decreased OEA mobilization in jejunum of lean rats, while feeding restores jejunal OEA levels (Rodriguez et al, 2001; Fu et al, 2007). Feeding-dependent OEA production is disrupted in gut of DIO rodents, suggesting that high-fat DIO is accompanied by alterations in post-digestive machinery responsible for OEA biosynthesis, which may contribute to reduced satiety and hyperphagia (Igarashi et al, 2015). Mechanistic understanding of intestinal OEA signaling in obesity will assist in the development of pharmacological strategies to control appetite in obesity.…”

Section: Homeostatic Regulation Of Energy Balancementioning

confidence: 99%

Obesity: Current and potential pharmacotherapeutics and targets

Narayanaswami

Dwoskin

2017

Pharmacology & Therapeutics

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155

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Obesity is a global epidemic that contributes to a number of health complications including cardiovascular disease, type 2 diabetes, cancer and neuropsychiatric disorders. Pharmacotherapeutic strategies to treat obesity are urgently needed. Research over the past two decades has increased substantially our knowledge of central and peripheral mechanisms underlying homeostatic energy balance. Homeostatic mechanisms involve multiple components including neuronal circuits, some originating in hypothalamus and brain stem, as well as peripherally-derived satiety, hunger and adiposity signals that modulate neural activity and regulate eating behavior. Dysregulation of one or more of these homeostatic components results in obesity. Coincident with obesity, reward mechanisms that regulate hedonic aspects of food intake override the homeostatic regulation of eating. In addition to functional interactions between homeostatic and reward systems in the regulation of food intake, homeostatic signals have the ability to alter vulnerability to drug abuse. Regarding the treatment of obesity, pharmacological monotherapies primarily focus on a single protein target. FDA-approved monotherapy options include phentermine (Adipex-P®), orlistat (Xenical®), lorcaserin (Belviq®) and liraglutide (Saxenda®). However, monotherapies have limited efficacy, in part due to the recruitment of alternate and counter-regulatory pathways. Consequently, a multi-target approach may provide greater benefit. Recently, two combination products have been approved by the FDA to treat obesity, including phentermine/topiramate (Qsymia®) and naltrexone/bupropion (Contrave®). The current review provides an overview of homeostatic and reward mechanisms that regulate energy balance, potential therapeutic targets for obesity and current treatment options, including some candidate therapeutics in clinical development. Finally, challenges in anti-obesity drug development are discussed.

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“…Interestingly, the changes in OEA production found in Magel2 -null mice are markedly different from those seen in mice that are made obese either by exposure to a high-fat diet or by genetic deletion of leptin ( ob / ob mice). In diet-induced obese mice, the enzymatic machinery involved in OEA formation is dramatically suppressed, whereas in ob / ob obese mice it remains unchanged [42,43]. …”

Section: Discussionmentioning

confidence: 99%

Dysfunctional oleoylethanolamide signaling in a mouse model of Prader-Willi syndrome

Igarashi

Narayanaswami

Kimonis

et al. 2017

Pharmacological Research

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Prader-Willi syndrome (PWS), the leading genetic cause of obesity, is characterized by a striking hyperphagic behavior that can lead to obesity, type-2 diabetes, cardiovascular disease and death. The molecular mechanism underlying impaired satiety in PWS is unknown. Oleoylethanolamide (OEA) is alipid mediator involved in the control of feeding, body weight and energy metabolism. OEA produced by small-intestinal enterocytes during dietary fat digestion activates type-α peroxisome proliferator-activated receptors (PPAR-α) to trigger an afferent signal that causes satiety. Emerging evidence from genetic and human laboratory studies suggests that deficits in OEA-mediated signaling might be implicated in human obesity. In the present study, we investigated whether OEA contributes to feeding dysregulation in Magel2m+/p− (Magel2 KO) mice, an animal model of PWS. Fasted/refed male Magel2 KO mice eat more than do their wild-type littermates and become overweight with age. Meal pattern analyses show that hyperphagia in Magel2 KO is due to increased meal size and meal duration rather than to lengthening of the intermeal interval, which is suggestive of a defect in mechanisms underlying satiation. Food-dependent OEA accumulation in jejunum and fasting OEA levels in plasma are significantly greater in Magel2 KO mice than in wild-type controls. Together, these findings indicate that deletion of the Magel2 gene is accompanied by marked changes in OEA signaling. Importantly, intraperitoneal administration of OEA (10 mg/kg) significantly reduces food intake in fasted/refed Magel2 KO mice, pointing to a possible use of this natural compound to control hunger in PWS.

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Feeding-induced oleoylethanolamide mobilization is disrupted in the gut of diet-induced obese rodents

Cited by 53 publications

References 45 publications

Association between plasma endocannabinoids and appetite in hemodialysis patients: A pilot study

Association between plasma endocannabinoids and appetite in hemodialysis patients: A pilot study

Obesity: Current and potential pharmacotherapeutics and targets

Dysfunctional oleoylethanolamide signaling in a mouse model of Prader-Willi syndrome

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