Characterization of the Hyperphagic Response to Dietary Fat in the MC4R Knockout Mouse

Srisai, Dollada; Gillum, Matthew P.; Panaro, Brandon L.; Zhang, Xian Man; Kotchabhakdi, Naiphinich; Shulman, Gerald I.; Ellacott, Kate L. J.; Cone, Roger D.

doi:10.1210/en.2010-0716

Cited by 64 publications

(67 citation statements)

References 38 publications

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“…For instance, the lower overall food intake appeared to be particularly driven by reductions in food intake during the dark phase (the active period), which was accompanied by shorter meal bouts and smaller meal size without an effect on intermeal intervals. This effect of pNAPE-EcN treatment on meal patterning for high-fat feeding differs somewhat from previous reports in chow-fed rats, in which increasing NAE levels decreased food intake primarily by increasing post-meal intervals and adiposity (15)(16)(17)(18)(19)(20)(21)(22)(23)(24). Biosynthesis of small-molecule therapeutic compounds like NAPEs may have several potential advantages over biosynthesis of anorexigenic peptides or the use of nonmodified probiotic bacteria.…”

Section: Discussioncontrasting

confidence: 80%

“…After their synthesis, NAPEs are rapidly converted to the active NAEs through hydrolysis by NAPEhydrolyzing phospholipase D (NAPE-PLD). Intraperitoneal administration of NAEs, where the N-acyl chains are saturated or monounsaturated (e.g., N-oleoyl-ethanolamide [OEA]), or of their precursors (e.g., C16:0NAPE) markedly reduces food intake and obesity in mice fed a high-fat diet (15)(16)(17)(18)(19)(20)(21)(22)(23)(24). Chronic NAE administration appears to modulate adiposity through multiple mechanisms including inhibition of fat absorption (25), delayed gastric emptying (26,27), reduced food intake (19,20,28,29), and increased fatty acid oxidation (23,25).…”

Section: Introductionmentioning

confidence: 99%

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Incorporation of therapeutically modified bacteria into gut microbiota inhibits obesity

Chen¹,

Guo²,

Zhang³

et al. 2014

J. Clin. Invest.

249

169

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Section: Discussioncontrasting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Incorporation of therapeutically modified bacteria into gut microbiota inhibits obesity

Chen¹,

Guo²,

Zhang³

et al. 2014

J. Clin. Invest.

249

169

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“…Having shown that MC4R deficiency confers reduced dietary preference for sucrose-rich food, we sought to test whether MC4R deficiency causes dietary fat preference consistent with the high-fat hyperphagia noted previously (15,16). To study these feeding behaviors, we used groups of WT, MC4R…”

Section: Mc4r −/− Mice Exhibit Low Preference For Palatable High-fat mentioning

confidence: 99%

“…5A). Following the initial period of novelty associated with the HFD presentation, all groups reached a steady level of intake of both SC and HFD by the second week of the two-choice diet (days [16][17][18][19][20][21][22]. The intake levels for both diets also remained unchanged after the position of each was switched (days 23-25), suggesting that the feeding preferences are not dependent upon location of the diets within the cage (Fig.…”

Section: Mc4r −/− Mice Exhibit Low Preference For Palatable High-fat mentioning

confidence: 99%

“…Previous studies have also characterized a significant stimulation of hyperphagia, persisting for up to 2 wk, in the MC4R −/− and +/− mice, following a switch from normal rodent chow (13.5% of kilocalories from fat) to a high-fat diet (HFD) (45-60% of kilocalories from fat) (15,16). In contrast, WT mice return to isocaloric intake within ∼4 d after the switch to HFD.…”

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confidence: 99%

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Melanocortin-4 receptor mutations paradoxically reduce preference for palatable foods

Panaro

Cone

2013

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

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Haploinsufficiency of the melanocortin-4 receptor (MC4R) results in melanocortin obesity syndrome, the most common monogenic cause of severe early onset obesity in humans. The syndrome, which produces measurable hyperphagia, has focused attention on the role of MC4R in feeding behavior and macronutrient intake. Studies show that inhibition of MC4R signaling can acutely increase the consumption of high-fat foods. The current study examines the chronic feeding preferences of mice with deletion of one or both alleles of the MC4R to model the human syndrome. Using twochoice diet paradigms with high-fat or high-carbohydrate foods alongside normal chow, we show, paradoxically, that deletion of one allele has no effect, whereas deletion of both alleles of the MC4R actually decreases preference for palatable high-fat and high-sucrose foods, compared with wild-type mice. Nonetheless, we observed hyperphagic behavior from increased consumption of the low-fat standard chow when either heterozygous or homozygous mutant animals were presented with dietary variety. Thus, decreased MC4R signaling in melanocortin obesity syndrome consistently yields hyperphagia irrespective of the foods provided, but the hyperphagia appears driven by variety and/or novelty, rather than by a preference for high-fat or high-carbohydrate foodstuffs.food preference | food intake | reward F ood preference in humans is highly complex, involving cultural, sociological, psychological, and physiological factors. Physiological inputs to food preference include both homeostatic and hedonic drives, with the latter referring to the effects of sensory and reward pathways that control the desire to consume highly palatable energy-dense foods (1). Profound hyperphagia has been demonstrated in several of the monogenic obesity syndromes (2), and it is important to determine the mechanisms that drive hyperphagia, including the relative contributions of homeostatic versus hedonic drives and their impact on food preference.Melanocortin obesity syndrome, resulting from null or hypomorphic mutations in one allele of the melanocortin-4 receptor (MC4R), is the most common monogenic cause of severe early onset obesity in humans (3, 4). The obese phenotype is due in large part to hyperphagia, which has been documented in humans (3) and in mouse (4, 5) and rat (6) models of the syndrome. Data also suggest that central melanocortin signaling may specifically regulate the consumption of dietary fats. The lethal yellow (A y /a) agouti mouse, in which ectopic expression of the agouti protein is presumed to block the central melanocortin-3 receptor (MC3R) and MC4R, shows a preference for fat consumption that is not seen in wild-type (WT) C57BL/6J mice on a three-choice macronutrient diet of carbohydrate, fat, or protein (7). Intracerebroventricular (ICV) administration of agouti-related protein (AgRP), an endogenous CNS antagonist of the MC3R and MC4R, preferentially increases acute consumption of high-fat chow in a two-choice paradigm providing high-fat and low-fat chow in Lo...

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Classical endocannabinoid‐like compounds and their regulation by nutrients

2014

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Endocannabinoid-like compounds are structurally related to the true endocannabinoids but do not contain highly unsaturated fatty acids, and they do not bind the cannabinoid receptors. The classical endocannabinoid-like compounds include N-acylethanolamines and 2-monoacylglycerols, and their structural resemblance to the endocannabinoids makes them players in the endocannabinoid system, where they can interfere with the actions of the true endocannabinoids, because they in several cases engage the same synthesizing and degrading enzymes. In addition they have pharmacological actions of their own, which are particularly interesting in a nutritional and metabolic context. Exogenously supplied oleoylethanolamide, palmitoylethanolamide, and linoleoylethanolamide have anorexic effects, and the endogenous formation of these N-acylethanolamines in the small intestine may serve an important role in regulating food intake, through signaling via PPARα and the vagus nerve to the brain appetite center. A chronic high-fat diet will decrease intestinal levels of these anorectic N-acylethanolamines and this may contribute to the hyperphagic effect of high-fat diet; 2-monoacylglycerols mediate endocrine responses in the small intestine; probably trough activation of GPR119 on enteroendocrine cells, and diet-derived 2-monoacylglycerols, for example, 2-oleoylglycerol and 2-palmitoylglycerol might be important for intestinal fat sensing. Whether these 2-monoacylglycerols have signaling functions in other tissues is unclear at present.

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Characterization of the Hyperphagic Response to Dietary Fat in the MC4R Knockout Mouse

Cited by 64 publications

References 38 publications

Incorporation of therapeutically modified bacteria into gut microbiota inhibits obesity

Incorporation of therapeutically modified bacteria into gut microbiota inhibits obesity

Melanocortin-4 receptor mutations paradoxically reduce preference for palatable foods

Classical endocannabinoid‐like compounds and their regulation by nutrients

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