Roger Cone

Roger Cone
University of Michigan | U-M · Life Sciences Institute

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245
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Publications

Publications (245)
Article
Full-text available
Effects of CRISPR/Cas9 knockout of the melanocortin-4 receptor (mc4r) gene in channel catfish, Ictalurus punctatus, were investigated. Three sgRNAs targeting the channel catfish mc4r gene in conjunction with Cas9 protein were microinjected in embryos and mutation rate, inheritance, and growth were studied. Efficient mutagenesis was achieved as demo...
Article
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...
Article
Full-text available
Melanocortin peptides containing a 3-(2-naphthyl)-d-alanine residue in position 7 (DNal(2')7), reported as melanocortin-3 receptor (MC3R) subtype-specific agonists in two separate publications, were found to lack significant MC3R agonist activity. The cell lines used at the University of Arizona for pharmacological characterization of these peptide...
Preprint
Channel catfish, Ictalurus punctatus , have limited ability to synthesize Ω-3 fatty acids due to a lack of elongases and desaturases. The ccβA-msElovl2 transgene containing masu salmon, Oncorhynchus masou , elongase gene driven by the common carp, Cyprinus carpio , beta-actin promoter was inserted into the channel catfish melanocortin-4 receptor (...
Preprint
Full-text available
Melanocortin peptides containing a D-naphthylalanine residue in position 7 (DNal(2')7), reported as melanocortin-3 receptor (MC3R) subtype-specific agonists in two separate publications, were found to lack significant MC3R agonist activity. The cell lines used at the University of Arizona for pharmacological characterization of these peptides, cons...
Article
Full-text available
The adipose tissue-derived hormone leptin can drive decreases in food intake while increasing energy expenditure. In diet-induced obesity, circulating leptin levels rise proportionally to adiposity. Despite this hyperleptinemia, rodents and humans with obesity maintain increased adiposity and are resistant to leptin’s actions. Here we show that inh...
Article
Full-text available
The state of somatic energy stores in metazoans is communicated to the brain, which regulates key aspects of behaviour, growth, nutrient partitioning and development1. The central melanocortin system acts through melanocortin 4 receptor (MC4R) to control appetite, food intake and energy expenditure2. Here we present evidence that MC3R regulates the...
Article
Background Genetics and biology may influence the age at onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to AN age at onset and to investigate the genetic associations between age at onset of AN and age at menarche. Methods A secondary analysis of the Psychiatric Genomics Consor...
Article
Work in recent decades has established that metabolic hormones released by endocrine cells and diverse other cell types serve to regulate nutrient intake and energy homeostasis. Tsukushi (TSK) is a leucine-rich repeat-containing protein secreted primarily by the liver that exerts an inhibitory effect on brown fat sympathetic innervation and thermog...
Article
CONTEXT Pro-opiomelanocortin (POMC) and the melanocortin-4 receptor (MC4R) play a pivotal role in the leptin-melanocortin pathway. Mutations in these genes lead to monogenic types of obesity due to severe hyperphagia. In addition to dietary-induced obesity, a cardiac phenotype without hypertrophy has been identified in MC4R knockout mice. OBJECTIV...
Article
Full-text available
Mutations in the melanocortin 4 receptor (MC4R) result in hyperphagia and obesity and are the most common cause of monogenic obesity in humans. Preclinical rodent studies have determined that the critical role of the MC4R in controlling feeding can be mapped in part to its expression in the paraventricular nucleus of the hypothalamus (paraventricul...
Article
Full-text available
Ablation of hypothalamic AgRP (Agouti-related protein) neurons is known to lead to fatal anorexia, whereas their activation stimulates voracious feeding and suppresses other motivational states including fear and anxiety. Despite the critical role of AgRP neurons in bidirectionally controlling feeding, there are currently no therapeutics available...
Article
The melanocortin receptors (MC1R-MC5R) belong to class A G-protein-coupled receptors (GPCRs) and are known to have receptor-specific roles in normal and diseased states. Selectivity for MC4R is of particular interest due to its involvement in various metabolic disorders, including obesity, feeding regulation, and sexual dysfunctions. To further imp...
Article
Full-text available
The melanocortin receptor accessory protein 2 (MRAP2) plays a pivotal role in the regulation of several G-protein coupled receptors (GPCR) that are essential for energy balance and food intake. MRAP2 loss-of-function results in obesity in mammals. MRAP2 and its homolog MRAP1 have an unusual membrane topology and are the only known eukaryotic protei...
Preprint
Full-text available
The melanocortin receptor accessory protein 2 (MRAP2) plays a pivotal role in the regulation of several G- protein coupled receptors (GPCR) that are essential for energy balance and food intake. MRAP2 loss-of-function results in obesity in mammals. MRAP2 and its homolog MRAP1 have an unusual membrane topology and are the only known eukaryotic prote...
Article
Full-text available
Overweight and obesity are global concerns affecting nearly one third of the world population. These conditions are characterized by increased adiposity and are accompanied by a proportional increase in circulating leptin, an anorexigenic adipokine. Leptin is responsible for signaling peripheral energy status to the central nervous system to modula...
Article
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The melanocortin-4 receptor (MC4R) is involved in energy homeostasis and is an important drug target for syndromic obesity. We report the structure of the antagonist SHU9119-bound human MC4R at 2.8-angstrom resolution. Ca2+ is identified as a cofactor that is complexed with residues from both the receptor and peptide ligand. Extracellular Ca2+ incr...
Article
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Eating disorders and substance use disorders frequently co‐occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [rg], twin‐based = 0.23‐0.53). We estimated the genetic correlation...
Article
Mutations in the melanocortin-4 receptor (MC4R) are the most common cause of early syndromic obesity known. Most of these mutations result in a loss of protein expression, α-melanocyte-stimulating hormone ( α -MSH) binding, receptor trafficking, or coupling to the stimulatory G-protein, G α s . However, approximately 26% of the obesity-associated...
Article
Full-text available
Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness¹, affecting 0.9–4% of women and 0.3% of men2–4, with twin-based heritability estimates of 50–60%⁵. Mortality rates are higher than those in other psychiatric disorders⁶, and outcomes are unacceptably poor⁷. Here we combine data from the Anorexia Nerv...
Article
Agouti-related protein (AgRP) is a hypothalamic regulator of food consumption in mammals. However, AgRP has also been detected in circulation, but a possible endocrine role has not been examined. Zebrafish possess two agrp genes: hypothalamically expressed agrp1, considered functionally equivalent to the single mammalian agrp, and agrp2, which is e...
Article
Energy stores in fat tissue are determined in part by the activity of hypothalamic neurons expressing the melanocortin‐4 receptor (MC4R). Even partial reduction in MC4R expression levels in mice, rats, or humans produces hyperphagia and morbid obesity. Thus, it is of great interest to understand the molecular basis of neuromodulation by the MC4R. T...
Article
Full-text available
Like most homeostatic systems, adiposity in mammals is defended between upper and lower boundary conditions. While leptin and melanocortin-4 receptor (MC4R) signaling are required for defending energy set point, mechanisms controlling upper and lower homeostatic boundaries are less well understood. In contrast to the MC4R, deletion of the MC3R does...
Article
The complete genome of the channel catfish, Ictalurus punctatus, has been sequenced, leading to greater opportunities for studying channel catfish gene function. Gene knockout has been used to study these gene functions in vivo. The clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9 (CRISPR/Cas9) system is a power...
Chapter
The family of inward rectifying potassium channels (Kir channels) plays crucial roles in the regulation of heart rhythms, renal excretion, insulin release, and neuronal activity. Their dysfunction has been attributed to numerous diseases such as cardiac arrhythmia, kidney failure and electrolyte imbalance, diabetes mellitus, epilepsy, retinal degen...
Article
Full-text available
Subjects spending much time sitting have increased risk of obesity but the mechanism for the antiobesity effect of standing is unknown. We hypothesized that there is a homeostatic regulation of body weight. We demonstrate that increased loading of rodents, achieved using capsules with different weights implanted in the abdomen or s.c. on the back,...
Data
Source data for Figure 7A and C, and 7E-H. This source file provides mean, SD, sample size and statistical test information for all studies presented in Figure 7.
Data
Source data for Figure 9A. This source file provides mean, SD, sample size and statistical test information for the Figure 9A western blot study an example of which is shown in Figure 9B.
Data
Source data for Figure 12B. This source file provides mean, SD, sample size and statistical test information for the doxorubicin studies outlined in Figure 12A and presented in Figure 12B.
Data
Source data for Figure 10A–D. This source file provides mean, SD, sample size and statistical test information for all ROS studies presented in Figure 10.
Data
Source data for Figure 1C–G and J-N. This source file provides mean, SD, sample size and statistical test information for all echocardiography analyses in Figure 1, of which examples are shown in Figure 1A–B and H-I.
Data
Source data for Figure 4A–B. This source file provides mean, SD, sample size and statistical test information for all qRT-PCR experiments in Figure 4.
Data
Source data for Figure 5A–G and K-O. This source file provides mean, SD, sample size and statistical test information for all body compostion, glucose tolerance, and echocardiography studies in Figure 5.
Data
Source data for Figure 3C–G. This source file provides mean, SD, sample size and statistical test information for all echocardiography analyses in Figure 3, of which examples are shown in Figure 3A–B.
Data
Source data for Figure 6B–D and 6F. This source file provides mean, SD, sample size and statistical test information for the gross pathological and histological analyses presented in Figure 6.
Data
Source data for Figure 8A–F. This source file provides mean, SD, sample size and statistical test information for all high resolution respirometry studies in Figure 8.
Data
Source data for Figure 11B. This source file provides mean, SD, sample size and statistical test information for the qRT-PCR studies presented in Figure 11B.
Article
Full-text available
Haploinsufficiency of the melanocortin-4 receptor, the most common monogenetic obesity syndrome in humans, is associated with a reduction in autonomic tone, bradycardia, and incidence of obesity-associated hypertension. Thus, it has been assumed that melanocortin obesity syndrome may be protective with respect to obesity-associated cardiovascular d...
Article
Full-text available
Anorexia nervosa (AN) is a complex neuropsychiatric disorder presenting with dangerously low body weight, and a deep and persistent fear of gaining weight. To date, only one genome-wide significant locus associated with AN has been identified. We performed an exome-chip based genome-wide association studies (GWAS) in 2158 cases from nine population...
Article
Full-text available
Objective: Pro-opiomelanocortin (POMC)-derived peptides act on neurons expressing the Melanocortin 4 receptor (MC4R) to reduce body weight. Setmelanotide is a highly potent MC4R agonist that leads to weight loss in diet-induced obese animals and in obese individuals with complete POMC deficiency. While POMC deficiency is very rare, 1–5% of severely...
Article
Full-text available
The neuropeptide agouti-related protein (AgRP) is expressed in the arcuate nucleus of the mammalian hypothalamus and plays a key role in regulating food consumption and energy homeostasis. Fish express two agrp genes in the brain: agrp1, considered functionally homologous with the mammalian AgRP, and agrp2. The role of agrp2 and its relationship to...
Article
The maintenance of normal body weight is disrupted in patients with anorexia nervosa (AN) for prolonged periods of time. Prior to the onset of AN, premorbid body mass index (BMI) spans the entire range from underweight to obese. After recovery, patients have reduced rates of overweight and obesity. As such, loci involved in body weight regulation m...
Article
Melanocortin signaling is regulated by the binding of naturally occurring antagonists, agouti-signaling protein (ASIP) and agouti-related protein (AGRP) that compete with melanocortin peptides by binding to melanocortin receptors to regulate energy balance and growth. Using a transgenic model overexpressing ASIP, we studied the involvement of melan...
Article
The melanocortin peptides derived from proopiomelanocortin (POMC) were originally understood in terms of the biological actions of α-melanocyte stimulating hormone (α-MSH) on pigmentation and adrenocorticotropic hormone (ACTH) on adrenocortical glucocorticoid production. However, the discovery of POMC mRNA and melanocortin peptides in the CNS gener...
Article
Leptin is the primary adipostatic factor in mammals. Produced largely by adipocytes in proportion to total adipose mass, the hormone informs the brain regarding total energy stored as triglycerides in fat cells. The hormone acts on multiple circuits in the brain to regulate food intake, autonomic outflow, and endocrine function to maintain energy b...
Article
Arcuate AgRP neurons are critical for food intake. Two pathways leading to AgRP neuron activation and food intake include regulation by peripheral hormones leptin and ghrelin, and neuronal regulation via glutamatergic inputs. In a recent article in Cell Reports, Yang et al. demonstrate 'a third way,' regulation by resident astrocytes. Copyright © 2...
Conference Paper
Evidence of leptin resistance is indicated by elevated leptin levels together with other hallmarks of obesity such as a defect in energy homeostasis.1 As obesity is an increasing epidemic in the US, the investigation of mechanisms by which leptin resistance has a pathophysiological impact on energy is an intensive field of research.2 However, the m...
Article
How does marijuana cause the irresistible hunger pangs known as the munchies? Paradoxically, the answer seems to involve an unusual mode of activation of a brain circuit best known for suppressing appetite. SEE ARTICLE P.45
Article
Context: Activation of the melanocortin-4 receptor (MC4R) with the synthetic agonist RM-493 decreases body weight and increases energy expenditure (EE) in nonhuman primates. The effects of MC4R agonists on EE in humans have not been examined to date. Objective, design, and setting: In a randomized, double-blind, placebo-controlled, crossover stu...
Article
Full-text available
The regulated release of anorexigenic α-melanocyte stimulating hormone (α-MSH) and orexigenic Agouti-related protein (AgRP) from discrete hypothalamic arcuate neurons onto common target sites in the central nervous system has a fundamental role in the regulation of energy homeostasis. Both peptides bind with high affinity to the melanocortin-4 rece...
Article
Full-text available
The melanocortin-4 receptor (MC4R) is expressed in the brainstem and vagal afferent nerves and regulates a number of aspects of gastrointestinal function. Here we show that the receptor is also diffusely expressed in cells of the gastrointestinal system, from stomach to descending colon. Furthermore, MC4R is the second most highly enriched GPCR in...
Article
Full-text available
The melanocortin-3 and -4 receptors (MC3R; MC4R) are known to play critical roles in energy homeostasis. However, the physiological functions of the MC3R remain poorly understood. Earlier reports indicated that the ventral tegmental area (VTA) is one of the highest sites of MC3R expression, and we sought to determine the function of the receptor in...
Article
The Wellcome Trust Case Control Consortium 3 anorexia nervosa genome-wide association scan includes 2907 cases from 15 different populations of European origin genotyped on the Illumina 670K chip. We compared methods for identifying population stratification, and suggest list of markers that may help to counter this problem. It is usual to identify...
Article
Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched contr...
Article
Mammalian ghrelin is a stomach-derived peptide that stimulates secretion of growth hormone and food intake. Zebrafish is an excellent model system for forward genetic studies, and many aspects of energy homeostasis characterized in mammals appear to be conserved in the zebrafish. In this study, we investigated the expression and regulation of zebra...
Article
The melanocortin-4 receptor (MC4R) is essential for control of energy homeostasis in vertebrates. MC4R interacts with melanocortin receptor accessory protein 2 (MRAP2) in vitro, but its functions in vivo are unknown. We found that MRAP2a, a larval form, stimulates growth of zebrafish by specifically blocking the action of MC4R. In cell culture, thi...
Article
Full-text available
Abstract Energy homeostasis is maintained by balancing energy intake and expenditure. Many signals regulating energy intake are conserved between the human and teleost. However, before this work, there was no sensitive high-throughput system to monitor energy expenditure in the teleost. We exploit the nonfluorescent and fluorescent properties of re...