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Malcolm J Low - One of the best experts on this subject based on the ideXlab platform.
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adult born Proopiomelanocortin neurons derived from rax expressing precursors mitigate the metabolic effects of congenital hypothalamic Proopiomelanocortin deficiency
Molecular metabolism, 2021Co-Authors: Gabor Wittmann, Malcolm J Low, Ronald M LechanAbstract:Abstract Objective Proopiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus are essential regulators of energy balance. Selective loss of POMC production in these cells results in extreme obesity and metabolic comorbidities. Neurogenesis occurs in the adult hypothalamus, but it remains uncertain whether functional POMC neurons emerge in physiologically significant numbers during adulthood. Here, we tested whether Rax-expressing precursors generate POMC neurons in adult mice and rescue the metabolic phenotype caused by congenital hypothalamic POMC deficiency. Methods Initially, we identified hypothalamic Rax-expressing cell types using wild-type and Rax-CreERT2:Ai34D mice. Then we generated compound Rax-CreERT2:ArcPomcloxTB/loxTB mice in which endogenous hypothalamic Pomc expression is silenced, but can be restored by tamoxifen administration selectively in neurons derived from Rax+ progenitors. The number of POMC neurons generated by Rax+ progenitors in adult mice and their axonal projections was determined. The metabolic effects of these neurons were assessed by measuring food intake, bodyweight, and body composition, along with glucose and insulin levels. Results We found that Rax is expressed by tanycytes and a previously unrecognized cell type in the hypothalamic parenchyma of adult mice. Rax+ progenitors generated ~10% of the normal adult hypothalamic POMC neuron population within two weeks of tamoxifen treatment. The same rate and steady state of POMC neurogenesis persisted from young adult to aged mice. These new POMC neurons established terminal projections to brain regions that were involved in energy homeostasis. Mice with Rax+ progenitor-derived POMC neurons had reduced body fat mass, improved glucose tolerance, increased insulin sensitivity, and decreased bodyweight in proportion to the number of new POMC neurons. Conclusions These data demonstrate that Rax+ progenitors generate POMC neurons in sufficient numbers during adulthood to mitigate the metabolic abnormalities of hypothalamic POMC-deficient mice. The findings suggest that adult hypothalamic neurogenesis is a robust phenomenon in mice that can significantly impact energy homeostasis.
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hypothalamic pomc deficiency impairs the function of leptin to decrease food intake and bodyweight
The FASEB Journal, 2016Co-Authors: Kavaljit H Chhabra, Jessica M Adams, Graham L Jones, Marcelo Rubinstein, Malcolm J LowAbstract:Proopiomelanocortin (Pomc) in the arcuate nucleus (Arc) of the hypothalamus is necessary for normal energy homeostasis; therefore, its deficiency leads to obesity. We recently reported that ArcPomc...
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temporal changes in nutritional state affect hypothalamic pomc peptide levels independently of leptin in adult male mice
American Journal of Physiology-endocrinology and Metabolism, 2014Co-Authors: Aaron J Mercer, Ronald C Stuart, Eduardo A Nillni, Courtney A Attard, Veronica Oterocorchon, Malcolm J LowAbstract:Hypothalamic Proopiomelanocortin (POMC) neurons constitute a critical anorexigenic node in the central nervous system (CNS) for maintaining energy balance. These neurons directly affect energy expe...
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unraveling the central Proopiomelanocortin neural circuits
Frontiers in Neuroscience, 2013Co-Authors: Aaron J Mercer, Shane T Hentges, Charles K Meshul, Malcolm J LowAbstract:Central Proopiomelanocortin (POMC) neurons form a potent anorexigenic network, but our understanding of the integration of this hypothalamic circuit throughout the central nervous system (CNS) remains incomplete. POMC neurons extend projections along the rostrocaudal axis of the brain, and can signal with both POMC-derived peptides and fast amino acid neurotransmitters. Although recent experimental advances in circuit-level manipulation have been applied to POMC neurons, many pivotal questions still remain: how and where do POMC neurons integrate metabolic information? Under what conditions do POMC neurons release bioactive molecules throughout the CNS? Are GABA and glutamate or neuropeptides released from POMC neurons more crucial for modulating feeding and metabolism? Resolving the exact stoichiometry of signals evoked from POMC neurons under different metabolic conditions therefore remains an ongoing endeavor. In this review, we analyze the anatomical atlas of this network juxtaposed to the physiological signaling of POMC neurons both in vitro and in vivo. We also consider novel genetic tools to further characterize the function of the POMC circuit in vivo. Our goal is to synthesize a global view of the POMC network, and to highlight gaps that require further research to expand our knowledge on how these neurons modulate energy balance.
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meal pattern analysis in neural specific Proopiomelanocortin deficient mice
European Journal of Pharmacology, 2011Co-Authors: Christian D Richard, Malcolm J Low, Virginie TolleAbstract:The central melanocortin system, consisting of melanocortin peptides, agouti gene related peptide and their receptors plays a critical role in the homeostatic control of energy balance. Loss of function mutations in the genes encoding Proopiomelanocortin or melanocortin MC4 receptors cause profound obesity and hyperphagia. However, little is known about the functional relationship of melanocortin neurocircuits to the temporal organization of meal-taking behavior. We used an operant paradigm that combined lever pressing for food pellet deliveries with free water intake monitored by lickometers to quantify meal patterns in mutant mice that selectively lack Proopiomelanocortin expression in hypothalamic neurons (nPOMCKO). Compared to wildtype siblings, nPOMCKO mice consumed 50% more food and water daily and exhibited a more stereotyped feeding pattern characterized by reduced inter-meal and inter-mouse variations. Average meals were larger in size but shorter in duration, with no change in meal number. Consequently, intermeal intervals were prolonged in nPOMCKO mice. Similar patterns were observed in pre-obese juvenile and frankly obese adult mice suggesting that neither age nor degree of obesity was responsible for the altered phenotypes. Spontaneous locomotion and wheel running were decreased in nPOMCKO mice, but circadian variations in locomotor and feeding activity were conserved. These data show that hyperphagia in male nPOMCKO mice is due to increased meal size but not meal number, and this pattern is established by age 5 wk. The combination of larger, more rapidly consumed meals and prolonged intermeal intervals suggests that Proopiomelanocortin peptides are necessary for normal meal termination, but not the maintenance of satiety.
Martin J Kelly - One of the best experts on this subject based on the ideXlab platform.
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estradiol protects Proopiomelanocortin neurons against insulin resistance
Endocrinology, 2018Co-Authors: Jian Qiu, Martha A Bosch, Cecilia Meza, Uyen Vy Navarro, Casey C Nestor, Edward J Wagner, Oline K Ronnekleiv, Martin J KellyAbstract:Insulin resistance is at the core of the metabolic syndrome, and men exhibit a higher incidence of metabolic syndrome than women in early adult life, but this sex advantage diminishes sharply when women reach the postmenopausal state. Because 17β-estradiol (E2) augments the excitability of the anorexigenic Proopiomelanocortin (POMC) neurons, we investigated the neuroprotective effects of E2 against insulin resistance in POMC neurons from diet-induced obese (DIO) female and male mice. The efficacy of insulin to activate canonical transient receptor potential 5 (TRPC5) channels and depolarize POMC neurons was significantly reduced in DIO male mice but not in DIO female mice. However, the insulin response in POMC neurons was abrogated in ovariectomized DIO females but restored with E2 replacement. E2 increased T-type calcium channel Cav3.1 messenger RNA (mRNA) expression and whole-cell currents but downregulated stromal-interaction molecule 1 mRNA, which rendered POMC neurons more excitable and responsive to insulin-mediated TRPC5 channel activation. Moreover, E2 prevented the increase in suppressor of cytokine signaling-3 mRNA expression with DIO as seen in DIO males. As proof of principle, insulin [intracerebroventricular injection into the third ventricle (ICV)] decreased food intake and increased metabolism in female but not male guinea pigs fed a high-fat diet. The uncoupling of the insulin receptor from its downstream effector system was corroborated by the reduced expression of phosphorylated protein kinase B in the arcuate nucleus of male but not female guinea pigs following insulin. Therefore, E2 protects female POMC neurons from insulin resistance by enhancing POMC neuronal excitability and the coupling of insulin receptor to TRPC5 channel activation.
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leptin excites Proopiomelanocortin neurons via activation of trpc channels
The Journal of Neuroscience, 2010Co-Authors: Jian Qiu, Yuan Fang, Oline K Ronnekleiv, Martin J KellyAbstract:Leptin can exert its potent appetite-suppressing effects via activation of hypothalamic Proopiomelanocortin (POMC) neurons. It depolarizes POMC neurons via activation of a yet unidentified nonselective cation current. Therefore, we sought to identify the conductance activated by leptin using whole-cell recording in EGFP-POMC neurons from transgenic mice. The TRPC channel blockers SKF96365 (1-[β-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1 H -imidazole hydrochloride), flufenamic acid, and 2-APB (2-aminoethyl diphenylborinate) potently inhibited the leptin-induced current. Also, lanthanum (La 3+ ) and intracellular Ca 2+ potentiated the effects of leptin. Moreover, the diacylglycerol-permeable analog OAG (2-acetyl-1-oleoyl-sn-glycerol) failed to activate any TRPC current. Using a Cs + -gluconate-based internal solution, the leptin-activated current reversed near −20 mV. After replacement of external Na + and K + with Cs + , the reversal shifted to near 0 mV, and the I / V curve exhibited a negative slope conductance at voltages more negative than −40 mV. Based on scRT-PCR, TRPC1 and TRPC4–7 mRNA were expressed in POMC neurons, with TRPC5 being the most prevalent. The leptin-induced current was blocked by the Jak2 inhibitor AG490, the PI3 kinase inhibitor wortmannin, and the phospholipase C inhibitors, U73122 and ET-18-OCH3. Notably, we identified PLCγ1 transcripts in the majority of POMC neurons. Therefore, leptin through a Jak2–PI3 kinase–PLCγ pathway activates TRPC channels, and TRPC1, 4, and 5 appear to be the key channels mediating the depolarizing effects of leptin in POMC neurons.
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leptin excites Proopiomelanocortin neurons via activation of trpc channels
The Journal of Neuroscience, 2010Co-Authors: Jian Qiu, Yuan Fang, Oline K Ronnekleiv, Martin J KellyAbstract:Leptin can exert its potent appetite-suppressing effects via activation of hypothalamic Proopiomelanocortin (POMC) neurons. It depolarizes POMC neurons via activation of a yet unidentified nonselective cation current. Therefore, we sought to identify the conductance activated by leptin using whole-cell recording in EGFP-POMC neurons from transgenic mice. The TRPC channel blockers SKF96365 (1-[beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole hydrochloride), flufenamic acid, and 2-APB (2-aminoethyl diphenylborinate) potently inhibited the leptin-induced current. Also, lanthanum (La(3+)) and intracellular Ca(2+) potentiated the effects of leptin. Moreover, the diacylglycerol-permeable analog OAG (2-acetyl-1-oleoyl-sn-glycerol) failed to activate any TRPC current. Using a Cs(+)-gluconate-based internal solution, the leptin-activated current reversed near -20 mV. After replacement of external Na(+) and K(+) with Cs(+), the reversal shifted to near 0 mV, and the I/V curve exhibited a negative slope conductance at voltages more negative than -40 mV. Based on scRT-PCR, TRPC1 and TRPC4-7 mRNA were expressed in POMC neurons, with TRPC5 being the most prevalent. The leptin-induced current was blocked by the Jak2 inhibitor AG490, the PI3 kinase inhibitor wortmannin, and the phospholipase C inhibitors, U73122 and ET-18-OCH3. Notably, we identified PLCgamma1 transcripts in the majority of POMC neurons. Therefore, leptin through a Jak2-PI3 kinase-PLCgamma pathway activates TRPC channels, and TRPC1, 4, and 5 appear to be the key channels mediating the depolarizing effects of leptin in POMC neurons.
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hypothalamic Proopiomelanocortin neurons are glucose responsive and express katp channels
Endocrinology, 2003Co-Authors: Nurhadi Ibrahim, Malcolm J Low, Marcelo Rubinstein, Jian Qiu, Martha A Bosch, Oline K Ronnekleiv, James L Smart, Martin J KellyAbstract:Hypothalamic Proopiomelanocortin (POMC) neurons are critical for controlling homeostatic functions in the mammal. We used a transgenic mouse model in which the POMC neurons were labeled with enhanced green fluorescent protein to perform visualized, whole-cell patch recordings from prepubertal female hypothalamic slices. The mouse POMC-enhanced green fluorescent protein neurons expressed the same endogenous conductances (a transient outward K(+) current and a hyperpolarization-activated, cation current) that have been described for guinea pig POMC neurons. In addition, the selective micro -opioid receptor agonist DAMGO induced an outward current (maximum of 12.8 +/- 1.2 pA), which reversed at K(+) equilibrium potential (E(K+)), in the majority (85%) of POMC neurons with an EC(50) of 102 nM. This response was blocked by the opioid receptor antagonist naloxone with an inhibition constant of 3.1 nM. In addition, the gamma-aminobutyric acid(B) receptor agonist baclofen (40 micro M) caused an outward current (21.6 +/- 4.0 pA) that reversed at E(K+) in these same neurons. The ATP-sensitive potassium channel opener diazoxide also induced an outward K(+) current (maximum of 18.7 +/- 2.2 pA) in the majority (92%) of POMC neurons with an EC(50) of 61 micro M. The response to diazoxide was blocked by the sulfonylurea tolbutamide, indicating that the POMC neurons express both Kir6.2 and sulfonylurea receptor 1 channel subunits, which was verified using single cell RT-PCR. This pharmacological and molecular profile suggested that POMC neurons might be sensitive to metabolic inhibition, and indeed, we found that their firing rate varied with changes in glucose concentrations. Therefore, it appears that POMC neurons may function as an integrator of metabolic cues and synaptic input for controlling homeostasis in the mammal.
Marcelo Rubinstein - One of the best experts on this subject based on the ideXlab platform.
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hypothalamic pomc deficiency impairs the function of leptin to decrease food intake and bodyweight
The FASEB Journal, 2016Co-Authors: Kavaljit H Chhabra, Jessica M Adams, Graham L Jones, Marcelo Rubinstein, Malcolm J LowAbstract:Proopiomelanocortin (Pomc) in the arcuate nucleus (Arc) of the hypothalamus is necessary for normal energy homeostasis; therefore, its deficiency leads to obesity. We recently reported that ArcPomc...
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hypothalamic Proopiomelanocortin neurons are glucose responsive and express katp channels
Endocrinology, 2003Co-Authors: Nurhadi Ibrahim, Malcolm J Low, Marcelo Rubinstein, Jian Qiu, Martha A Bosch, Oline K Ronnekleiv, James L Smart, Martin J KellyAbstract:Hypothalamic Proopiomelanocortin (POMC) neurons are critical for controlling homeostatic functions in the mammal. We used a transgenic mouse model in which the POMC neurons were labeled with enhanced green fluorescent protein to perform visualized, whole-cell patch recordings from prepubertal female hypothalamic slices. The mouse POMC-enhanced green fluorescent protein neurons expressed the same endogenous conductances (a transient outward K(+) current and a hyperpolarization-activated, cation current) that have been described for guinea pig POMC neurons. In addition, the selective micro -opioid receptor agonist DAMGO induced an outward current (maximum of 12.8 +/- 1.2 pA), which reversed at K(+) equilibrium potential (E(K+)), in the majority (85%) of POMC neurons with an EC(50) of 102 nM. This response was blocked by the opioid receptor antagonist naloxone with an inhibition constant of 3.1 nM. In addition, the gamma-aminobutyric acid(B) receptor agonist baclofen (40 micro M) caused an outward current (21.6 +/- 4.0 pA) that reversed at E(K+) in these same neurons. The ATP-sensitive potassium channel opener diazoxide also induced an outward K(+) current (maximum of 18.7 +/- 2.2 pA) in the majority (92%) of POMC neurons with an EC(50) of 61 micro M. The response to diazoxide was blocked by the sulfonylurea tolbutamide, indicating that the POMC neurons express both Kir6.2 and sulfonylurea receptor 1 channel subunits, which was verified using single cell RT-PCR. This pharmacological and molecular profile suggested that POMC neurons might be sensitive to metabolic inhibition, and indeed, we found that their firing rate varied with changes in glucose concentrations. Therefore, it appears that POMC neurons may function as an integrator of metabolic cues and synaptic input for controlling homeostasis in the mammal.
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absence of opioid stress induced analgesia in mice lacking beta endorphin by site directed mutagenesis
Proceedings of the National Academy of Sciences of the United States of America, 1996Co-Authors: Marcelo Rubinstein, Jeffrey S Mogil, M Japon, E C Chan, Richard G Allen, Malcolm J LowAbstract:A physiological role for beta-endorphin in endogenous pain inhibition was investigated by targeted mutagenesis of the Proopiomelanocortin gene in mouse embryonic stem cells. The tyrosine codon at position 179 of the Proopiomelanocortin gene was converted to a premature translational stop codon. The resulting transgenic mice display no overt developmental or behavioral alterations and have a normally functioning hypothalamic-pituitary-adrenal axis. Homozygous transgenic mice with a selective deficiency of beta-endorphin exhibit normal analgesia in response to morphine, indicating the presence of functional mu-opiate receptors. However, these mice lack the opioid (naloxone reversible) analgesia induced by mild swim stress. Mutant mice also display significantly greater nonopioid analgesia in response to cold water swim stress compared with controls and display paradoxical naloxone-induced analgesia. These changes may reflect compensatory upregulation of alternative pain inhibitory mechanisms.
Robert M Dores - One of the best experts on this subject based on the ideXlab platform.
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analyzing the radiation of the melanocortins in amphibians cloning of pomc cdnas from the pituitary of the urodele amphibians amphiuma means and necturus maculosus
Peptides, 2005Co-Authors: Katarzyna Kozak, David Costantino, Stephanie Lecaude, Cristina Sollars, Phillip B. Danielson, Robert M DoresAbstract:Proopiomelanocortin (POMC) cDNAs were cloned and sequenced from brain extracts of two species of urodele amphibians: Amphiuma means and Necturus maculosus. Although the two species of urodele amphibians belong to separate families, and do not share a direct common ancestor, the level of primary sequence identity for the open reading of the POMC cDNAs was 90% at the amino acid level and 79% at the nucleotide level. It appears that the POMC gene in these urodele amphibians has been accumulating mutations at the amino acid level at a slower rate than the POMC gene in other sarcopterygian orders.
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trends in the evolution of the Proopiomelanocortin gene
General and Comparative Endocrinology, 2005Co-Authors: Robert M Dores, Stephanie LecaudeAbstract:Abstract The POMC gene is perhaps the most extensively studied member of the opioid/orphanin gene family. In Phylum Chordata this gene has been characterized in representatives of every class within the Gnathostomata, as well as in one representative agnathan vertebrate, the marine lamprey. This review provides a systematic overview of trends in the evolution of the melanocortins (ACTH/α-MSH, β-MSH, γ-MSH, and δ-MSH) and β-endorphin in gnathostomes, and advances the hypothesis that the appearance of γ-MSH occurred early in the radiation of the gnathostomes. A summary of the extensive work on POMC genes in the marine lamprey is also provided, as well as a reevaluation of the conserved regions in the sequence of CLIP (corticotropin-like-intermediate lobe peptide) in the POMC sequences of the various groups of gnathostomes.
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cloning of Proopiomelanocortin from the brain of the african lungfish protopterus annectens and the brain of the western spadefoot toad spea multiplicatus
Neuroendocrinology, 1999Co-Authors: Stephanie Lecaude, Cristina Sollars, Jasem Alrubaian, Isabelle Lihrmann, Phillip B. Danielson, Hubert Vaudry, Catherine R. Propper, Robert M DoresAbstract:A degenerate primer, specific for the opioid core sequence YGGFM, was used to clone and sequence Proopiomelanocortin (POMC) cDNAs from the brain of the African lungfish, Protopterus annectens
Andrzej Slominski - One of the best experts on this subject based on the ideXlab platform.
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corticotropin releasing hormone and Proopiomelanocortin involvement in the cutaneous response to stress
Physical Review, 2000Co-Authors: Andrzej Slominski, Thomas A. Luger, Jacobo Wortsman, Ralf Paus, Samuel SolomonAbstract:The skin is a known target organ for the Proopiomelanocortin (POMC)-derived neuropeptides α-melanocyte stimulating hormone (α-MSH), β-endorphin, and ACTH and also a source of these peptides. Skin e...
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The expression of Proopiomelanocortin (POMC) and of corticotropin releasing hormone receptor (CRH-R) genes in mouse skin
Biochimica et biophysica acta, 1996Co-Authors: Andrzej Slominski, Gennady Ermak, Jim Hwang, Joseph E. Mazurkiewicz, David Corliss, Allison Y. EastmanAbstract:The Proopiomelanocortin (POMC) and the corticotropin releasing hormone receptor (CRH-R) genes are expressed in the skin of the C57BL/6 mouse throughout the entire hair cycle, and CRH immunoreactivity is present in the pilosebaceous unit of the hair follicle and the epidermis. These findings suggest that some components of hypothalamo-pituitary axis are operating in mouse skin.
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ultraviolet b and melanocyte stimulating hormone msh stimulate mrna production for msh receptors and Proopiomelanocortin derived peptides in mouse melanoma cells and transformed keratinocytes
Journal of Investigative Dermatology, 1995Co-Authors: Ashok K. Chakraborty, Andrzej Slominski, Gennady Ermak, Jim Hwang, John M PawelekAbstract:Cell lines of cutaneous origin, namely melanocytes and keratinocytes, were previously demonstrated to exhibit functional melanocyte-stimulating hormone (MSH) receptors that are up-regulated by ultraviolet (UV) radiation and by MSH itself. In this study, it is demonstrated that UVB irradiation, exposure to MSH, or exposure to N 6 ,O 2 -dibutyryl cyclic adenosine monophosphate stimulates production of mRNAs for both αMSH receptors and Proopiomelanocortin in cultured mouse Cloudman S91 melanoma cells, and that UVB stimulates production and release of MSH and adrenocorticotropin peptides in both melanoma cells and transformed PAM 212 mouse keratinocytes. The results add support to the hypothesis that the effects of UVB on cutaneous melanogenesis are mediated through a series of coordinated events in which MSH receptors and Proopiomelanocortin-derived peptides play a central role.
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Proopiomelanocortin, corticotropin releasing hormone and corticotropin releasing hormone receptor genes are expressed in human skin
FEBS letters, 1995Co-Authors: Andrzej Slominski, Gennady Ermak, Jim Hwang, Ashok K. Chakraborty, Joseph E. Mazurkiewicz, Martin C. MihmAbstract:Abstract Evidence is provided that human skin, the largest body organ exposed to multiple stressors, expresses Proopiomelanocortin (POMC), corticotropin releasing hormone (CRH) and CRH-receptor (CRHR) genes in vivo. In vitro studies show that POMC and CRHR mRNAs are transcribed in melanocytes, cells derived from the neural crest, and in keratinocytes, cells derived from the ectoderm. CRH mRNA is transcribed in cultured melanocytes but not in keratinocytes. It is proposed that an equivalent of the ‘hypothalamus-pituitary axis’ composed of the CRH-CRHR-POMC loop is conserved in mammalian skin.
