Genetic Dissection of the Functions of the Melanocortin-3 Receptor, a Seven-transmembrane G-protein-coupled Receptor, Suggests Roles for Central and Peripheral Receptors in Energy Homeostasis

Begriche, Karima; Levasseur, Peter R.; Zhang, Jingying; Rossi, Jari; Skorupa, Danielle; Solt, Laura A.; Young, Brandon; Burris, Thomas P.; Marks, Daniel L.; Mynatt, Randall L.; Butler, Andrew A.

doi:10.1074/jbc.m111.278374

Cited by 55 publications

(104 citation statements)

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“…15 The published results used female mice; our unpublished data suggest a similar outcome in male mice, whereas preliminary observations of male mice where the Nestin-Cre transgene was used to restore the expression of the LoxTB Mc3r allele in the nervous system suggest that FAA is rescued. These intriguing results suggest a functional divergence between neural and non-neural MC3Rs.…”

Section: Restoring the Loxtb Mc3r Allele In The Nervous System Does Nmentioning

confidence: 89%

“…Both Sf1-Cre; Mc3r TB/TB and Mc3r TB/TB mice exhibited attenuated FAA, indicating that the VMH MC3Rs are not sufficient to restore the expression of this complex group of behaviours. 15 In retrospect, this outcome is not that surprising, as data published over the past 10 years indicate that the VMH does not contain a 'FEO'. 71 Indeed, although some studies suggest that the anticipatory response to feeding involves the dorsomedial hypothalamus, 71--75 it has been debated whether the FEO resides in a single, definable structure.…”

Section: A Role For Melanocortin-3 Receptors In the Defence Of Body Wmentioning

confidence: 89%

“…16,17 Moreover, although the SF1-Cre transgene improved metabolic homeostasis, it did not improve FAA. 15 What was also remarkable about the metabolic phenotype of the Mc3rÀ/À mice used in our studies was that severe metabolic disturbances develop after the mice are subjected to RF. Weight loss associated with RF actually improved the metabolic phenotype of the lethal yellow A y /a strain, which develops obesity and severe glucose intolerance owing to ubiquitous expression of the agouti protein, an MC1R and MC4R antagonist.…”

Section: A Role For Melanocortin-3 Receptors In the Defence Of Body Wmentioning

confidence: 94%

“…We and others have also reported an adiposity phenotype, with reduced lean mass and increased fat mass. 15,91,92 We are currently determining whether restoring the expression of the LoxTB Mc3r allele using another neural-selective Cre strain results in similar outcomes.…”

Section: Restoring the Loxtb Mc3r Allele In The Nervous System Does Nmentioning

confidence: 99%

“…Homozygous carriers of the 'blocked' allele (Mc3r TB/TB ) exhibit undetectable levels of Mc3r expression in the brain and have the same obesity phenotype previously reported for Mc3rÀ/À mice: increased fat mass, reduced lean mass and accelerated diet-induced obesity. 15 VMH Mc3r expression was rescued using the steroidogenic factor-1 (SF-1) Cre mouse used by several laboratories to target this nucleus. Both Sf1-Cre; Mc3r TB/TB and Mc3r TB/TB mice exhibited attenuated FAA, indicating that the VMH MC3Rs are not sufficient to restore the expression of this complex group of behaviours.…”

Section: A Role For Melanocortin-3 Receptors In the Defence Of Body Wmentioning

confidence: 99%

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Unravelling the mysterious roles of melanocortin-3 receptors in metabolic homeostasis and obesity using mouse genetics

et al. 2014

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The central nervous melanocortin system maintains body mass and adiposity within a 'healthy' range by regulating satiety and metabolic homeostasis. Neural melanocortin-4 receptors (MC4R) modulate satiety signals and regulate autonomic outputs governing glucose and lipid metabolism in the periphery. The functions of melanocortin-3 receptors (MC3R) have been less well defined. We have observed that food anticipatory activity (FAA) is attenuated in Mc3rÀ/À mice housed in light:dark or constant dark conditions. Mc3rÀ/À mice subjected to the restricted feeding protocol that was used to induce FAA also developed insulin resistance, dyslipidaemia, impaired glucose tolerance and evidence of a cellular stress response in the liver. MC3Rs may thus function as modulators of oscillator systems that govern circadian rhythms, integrating signals from nutrient sensors to facilitate synchronizing peak foraging behaviour and metabolic efficiency with nutrient availability. To dissect the functions of MC3Rs expressed in hypothalamic and extra-hypothalamic structures, we inserted a 'lox-stop-lox' (TB) sequence into the Mc3r gene. Mc3r TB/TB mice recapitulate the phenotype reported for Mc3rÀ/À mice: increased adiposity, accelerated diet-induced obesity and attenuated FAA. The ventromedial hypothalamus exhibits high levels of Mc3r expression; however, restoring the expression of the LoxTB Mc3r allele in this nucleus did not restore FAA. However, a surprising outcome came from studies using Nestin-Cre to restore the expression of the LoxTB Mc3r allele in the nervous system. These data suggest that 'non-neural' MC3Rs have a role in the defence of body weight. Future studies examining the homeostatic functions of MC3Rs should therefore consider actions outside the central nervous system.International Journal of Obesity Supplements (2014) 4, S37--S44; doi:10.1038/ijosup.2014.10Keywords: melanocortin; metabolism; glucose; lipids; hypothalamus; feeding The central nervous melanocortin system forms a neural 'nutrientsensing' network, connecting signals of metabolic state with centres of the brain that regulate ingestive behaviours and metabolic homeostasis. 1 Genetic screens using morbidly obese individuals identified carriers with mutations in the melanocortin system, indicating that studying the melanocortin system has clinical relevance. 2 Nonsense mutations in the Proopiomelanocortin (POMC) gene 3 or the melanocortin-4 receptor (MC4R) gene are associated with hyperphagia and obesity. 4,5 MC3R mutations have also been suggested to be a predisposing factor for excessive weight gain, 6 although the association between MC3R mutations and obesity is less clear when compared with MC4R mutations.Data obtained from human genetics and animal models suggested that further study of the central nervous melanocortin system, and particularly MC4Rs, could lead to new therapies against obesity. 7 Although this outcome has yet to be realized, the information gathered from investigating this system significantly advanced the understanding of neural syst...

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Section: Restoring the Loxtb Mc3r Allele In The Nervous System Does Nmentioning

confidence: 89%

Section: A Role For Melanocortin-3 Receptors In the Defence Of Body Wmentioning

confidence: 89%

Section: A Role For Melanocortin-3 Receptors In the Defence Of Body Wmentioning

confidence: 94%

Section: Restoring the Loxtb Mc3r Allele In The Nervous System Does Nmentioning

confidence: 99%

Section: A Role For Melanocortin-3 Receptors In the Defence Of Body Wmentioning

confidence: 99%

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Unravelling the mysterious roles of melanocortin-3 receptors in metabolic homeostasis and obesity using mouse genetics

et al. 2014

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Comparison of vertebrate skin structure at class level: A review

Akat

Yenmiş

Pombal

et al. 2022

The Anatomical Record

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The skin is a barrier between the internal and external environment of an organism. Depending on the species, it participates in multiple functions. The skin is the organ that holds the body together, covers and protects it, and provides communication with its environment. It is also the body's primary line of defense, especially for anamniotes. All vertebrates have multilayered skin composed of three main layers: the epidermis, the dermis, and the hypodermis. The vital mission of the integument in aquatic vertebrates is mucus secretion. Cornification began in apmhibians, improved in reptilians, and endured in avian and mammalian epidermis. The feather, the most ostentatious and functional structure of avian skin, evolved in the Mesozoic period. After the extinction of the dinosaurs, birds continued to diversify, followed by the enlargement, expansion, and diversification of mammals, which brings us to the most complicated skin organization of mammals with differing glands, cells, physiological pathways, and the evolution of hair. Throughout these radical changes, some features were preserved among classes such as basic dermal structure, pigment cell types, basic coloration genetics, and similar sensory features, which enable us to track the evolutionary path. The structural and physiological properties of the skin in all classes of vertebrates are presented. The purpose of this review is to go all the way back to the agnathans and follow the path step by step up to mammals to provide a comparative large and updated survey about vertebrate skin in terms of morphology, physiology, genetics, ecology, and immunology.

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Organization of neural systems expressing melanocortin‐3 receptors in the mouse brain: Evidence for sexual dimorphism

Bedenbaugh

Brener

Maldonado

et al. 2022

J of Comparative Neurology

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The central melanocortin system is fundamentally important for controlling food intake and energy homeostasis. Melanocortin-3 receptor (MC3R) is one of two major receptors of the melanocortin system found in the brain. In contrast to the well-characterized melanocortin-4 receptor (MC4R), little is known regarding the organization of MC3R-expressing neural circuits. To increase our understanding of the intrinsic organization of MC3R neural circuits, identify specific differences between males and females, and gain a neural systems level perspective of this circuitry, we conducted a brain-wide mapping of neurons labeled for MC3R and characterized the distribution of their projections. Analysis revealed MC3R neuronal and terminal

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Genetic Dissection of the Functions of the Melanocortin-3 Receptor, a Seven-transmembrane G-protein-coupled Receptor, Suggests Roles for Central and Peripheral Receptors in Energy Homeostasis

Cited by 55 publications

References 58 publications

Unravelling the mysterious roles of melanocortin-3 receptors in metabolic homeostasis and obesity using mouse genetics

Unravelling the mysterious roles of melanocortin-3 receptors in metabolic homeostasis and obesity using mouse genetics

Comparison of vertebrate skin structure at class level: A review

Organization of neural systems expressing melanocortin‐3 receptors in the mouse brain: Evidence for sexual dimorphism

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