A Deletion in the Canine POMC Gene Is Associated with Weight and Appetite in Obesity-Prone Labrador Retriever Dogs

Raffan, Eleanor; Dennis, Rowena J.; O’Donovan, Conor J.; Becker, Julia; Scott, Robert A.; Smith, Stephen; Withers, David; Wood, Claire J.; Conci, Elena; Clements, Dylan; Summers, Kim M.; German, Alexander J.; Mellersh, Cathryn S.; Arendt, Maja L.; Iyemere, Valentine P.; Withers, Elaine; Söder, Josefin; Wernersson, Sara; Andersson, Gerhard; Lindblad‐Toh, Kerstin; Yeo, Giles S.H.; O’Rahilly, Stephen

doi:10.1016/j.cmet.2016.04.012

Cited by 123 publications

(141 citation statements)

References 30 publications

(41 reference statements)

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“…Th e anorexigenic eff ect of POMC has been proven by an increase in the food intake and adiposity as a result of POMC gene mutations in humans (Krude et al 1998) and gene deletion in canine (Raff an et al 2016). In the ARC nucleus, the cleavage of POMC results in the production of melanocortin peptides including adrenocorticotropic hormone (ACTH) and α-melanocyte-stimulating hormone (α-MSH) that exert their eff ects by binding to G-protein coupled melanocortin receptors (MC-Rs).…”

Section: Th E Hypothalamus Role In the Food Intake Controlmentioning

confidence: 99%

Central and peripheral control of food intake

Abdalla

2017

Endocrine Regulations

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Th e maintenance of the body weight at a stable level is a major determinant in keeping the higher animals and mammals survive. Th e body weight depends on the balance between the energy intake and energy expenditure. Increased food intake over the energy expenditure of prolonged time period results in an obesity. Th e obesity has become an important worldwide health problem, even at low levels. Th e obesity has an evil eff ect on the health and is associated with a shorter life expectancy. A complex of central and peripheral physiological signals is involved in the control of the food intake. Centrally, the food intake is controlled by the hypothalamus, the brainstem, and endocannabinoids and peripherally by the satiety and adiposity signals. Comprehension of the signals that control food intake and energy balance may open a new therapeutic approaches directed against the obesity and its associated complications, as is the insulin resistance and others. In conclusion, the present review summarizes the current knowledge about the complex system of the peripheral and central regulatory mechanisms of food intake and their potential therapeutic implications in the treatment of obesity. Th e maintenance of the body weight at a stable level is a major determinant in keeping the higher animals and mammals survive (Jequier and Tappy 1999). As a compensatory mechanism, hunger increases and energy expenditure decreases the weight loss. However, opposite responses are triggered when body weight increases. Body weight can change only when energy intake is not equal to energy expenditure over a given period of time (Bray et al. 2012). A complex physiological control system is involved in the maintenance of the energy balance. Th is system includes aff erent signals from the periphery about the state of the energy stores and eff erent signals that affect the energy intake and expenditure (Sandoval et al. 2008). Th is regulatory system is formed by multiple interactions between the gastrointestinal tract (GIT), adipose tissue, and the central nervous system (CNS). It is infl uenced by behavioral, sensorial, autonomic, nutritional, and endocrine mechanisms (Boguszewski et al. 2010). Satiety and adiposity signalsTh e food intake control includes a short-term regulation, which determines the beginning and the end of a meal (hunger and satiation) and the interval between the meals (satiety) and a long-term regulation with factors (signals of adiposity), which help to regulate the body energy depots (Cummings and Overduin 2007).Th e satiation means a suppression of the hunger and termination of the food intake aft er ingestion of Unauthenticated Download Date | 5/11/18 9:54 AM

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Section: Th E Hypothalamus Role In the Food Intake Controlmentioning

confidence: 99%

Central and peripheral control of food intake

Abdalla

2017

Endocrine Regulations

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“…NPY deficiency attenuates responses to a palatable high fat diet in mice (Hollopeter et al, 1998;Patel et al, 2006). Animals in which POMC neurons have been knocked out are obese and hyperphagic (Butler and Cone, 2002;Mencarelli et al, 2012;Diané et al, 2014;Raffan et al, 2016). Additionally, the release of these neuropeptides is closely associated with dietary fat level.…”

Section: Introductionmentioning

confidence: 99%

Dietary fat alters the response of hypothalamic neuropeptide Y to subsequent energy intake in broiler chickens

Wang

Liu

et al. 2016

Journal of Experimental Biology

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Dietary fat affects appetite and appetite-related peptides in birds and mammals; however, the effect of dietary fat on appetite is still unclear in chickens faced with different energy statuses. Two experiments were conducted to investigate the effects of dietary fat on food intake and hypothalamic neuropeptides in chickens subjected to two feeding states or two diets. In Experiment 1, chickens were fed a high-fat (HF) or low-fat (LF) diet for 35 days, and then subjected to fed (HF-fed, LF-fed) or fasted (HF-fasted, LF-fasted) conditions for 24 h. In Experiment 2, chickens that were fed a HF or LF diet for 35 days were fasted for 24 h and then re-fed with HF (HF-RHF, LF-RHF) or LF (HF-RLF, LF-RLF) diet for 3 h. The results showed that chickens fed a HF diet for 35 days had increased body fat deposition despite decreasing food intake even when the diet was altered during the re-feeding period (P<0.05). LF diet (35 days) promoted agouti-related peptide (AgRP) expression compared with HF diet (P<0.05) under both fed and fasted conditions. LF-RHF chickens had lower neuropeptide Y (NPY) expression compared with LF-RLF chickens; conversely, HF-RHF chickens had higher NPY expression than HF-RLF chickens (P<0.05). These results demonstrate: (1) that HF diet decreases food intake even when the subsequent diet is altered; (2) the orexigenic effect of hypothalamic AgRP; and (3) that dietary fat alters the response of hypothalamic NPY to subsequent energy intake. These findings provide a novel view of the metabolic perturbations associated with long-term dietary fat over-ingestion in chickens.

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“…S1E). hPSC-derived hypothalamic neurons produce b-MSH (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18) and other POMC-derived peptides…”

Section: Human Hypothalamic Neurons Appropriately Traffic and Secretementioning

confidence: 99%

“…Is POMC processing in human hypothalamic neurons regulated by exogenous factors such as leptin ? We found that hPSC-derived hypothalamic neurons trafficked and secreted POMC and its derivatives, and appropriately processed POMC into neuropeptides previously established to regulate energy balance, both in vitro and in vivo. These neuropeptides included b-MSH (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). We next developed quantitative assays for POMC-derived peptides and found that acetylated a-MSH was present at substantially (5- to 200- fold) lower concentrations than da-MSH, b-MSH, or b-EP.…”

Section: Introductionmentioning

confidence: 99%

“…POMC is also processed into b-endorphin (b-EP(1-31)) 9,10 which stimulates the µ-opioid receptor to promote analgesia and increased food intake [11][12][13] . Human hypothalamic POMC neurons might also produce b-MSH 14 , which is associated with human obesity when mutated [15][16][17] and inhibits feeding as potently as a-MSH when injected into mice 17 by activating MC4R [16][17][18] . However, b-MSH is not produced in the rodent brain and its existence and biological relevance in humans is controversial [19][20][21] .…”

Section: Introductionmentioning

confidence: 99%

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Human POMC processing in vitro and in vivo revealed by quantitative peptidomics

Kirwan

Kay

Brouwers

et al. 2018

Preprint

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Human obesity can result from the aberrant production or processing of proopiomelanocortin (POMC) in hypothalamic neurons, but it is unclear which human POMC-derived peptides are most relevant to body weight regulation. To address this question, we analysed both hypothalamic neurons derived from human pluripotent stem cells (hPSCs) and primary human hypothalamic tissue using quantitative liquid chromatography tandem mass spectroscopy (LC-MS/MS). In both in vitro-and in vivo-derived samples, we found that POMC was processed into b-melanocyte stimulating hormone (b-MSH), whose existence in the human brain has been controversial. b-MSH and desacetyl a-MSH (d-a-MSH) were produced at roughly equimolar concentrations and in vast excess to acetylated a-MSH (5-to 200-fold), suggesting that the importance of both d-a-MSH and b-MSH to human obesity has been underestimated. Since body weight is sensitive to changes in MSH concentration, we asked whether hPSC-derived hypothalamic neurons could provide mechanistic insights into the processing and secretion of MSH peptides. We found that cultured human hypothalamic neurons appropriately trafficked POMC and its derivatives, and robustly (P<0.0001) secreted them when depolarised. Furthermore, the adipocyte-derived hormone leptin significantly (P<0.01) promoted their production of both d-a-MSH and b-MSH. These results establish hPSC-derived hypothalamic neurons as a model system for studying human-specific aspects of POMC processing that might be therapeutically harnessed to treat obesity.

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A Deletion in the Canine POMC Gene Is Associated with Weight and Appetite in Obesity-Prone Labrador Retriever Dogs

Cited by 123 publications

References 30 publications

Central and peripheral control of food intake

Central and peripheral control of food intake

Dietary fat alters the response of hypothalamic neuropeptide Y to subsequent energy intake in broiler chickens

Human POMC processing in vitro and in vivo revealed by quantitative peptidomics

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