A Synergistic Antiobesity Effect by a Combination of Capsinoids and Cold Temperature Through Promoting Beige Adipocyte Biogenesis.

Beige adipocytes emerge postnatally within the white adipose tissue in response to certain environmental cues, such as chronic cold exposure. Because of its highly recruitable nature and relevance to adult humans, beige adipocytes have gained much attention as an attractive cellular target for antiobesity therapy. However, molecular circuits that preferentially promote beige adipocyte biogenesis remain poorly understood. We report that a combination of mild cold exposure at 17°C and capsinoids, a nonpungent analog of capsaicin, synergistically and preferentially promotes beige adipocyte biogenesis and ameliorates diet-induced obesity. Gain- and loss-of-function studies show that the combination of capsinoids and cold exposure synergistically promotes beige adipocyte development through the ß2-adrenoceptor signaling pathway. This synergistic effect on beige adipocyte biogenesis occurs through an increased half-life of PRDM16, a dominant transcriptional regulator of brown/beige adipocyte development. We document a previously unappreciated molecular circuit that controls beige adipocyte biogenesis and suggest a plausible approach to increase whole-body energy expenditure by combining dietary components and environmental cues.

Pimentas do gênero Capsicum: propriedades e ações terapéuticas / Pimientos del género Capsicum: propiedades y acciones terapéuticas / Capsicum peppers: properties and therapeutic actions

As especies do genero Capsicum L. vem sendo estudadas por pesquisadores do mundo inteiro. A pungencia e o atributo principal das pimentas e as substancias responséveis por esta ardencia sao denominadas de capsaicinoides. O mais estudado ea capsaicina, sua rota biossintetica e atraves da via dos fenilpropanoides e écidos graxos. A capsaicina e um agonista exogeno do receptor TRPV1(transient receptor potential vanilloid type-7). O TRPV1 contem uma subunidade sensivel ao calor responsével pela sensaçao de queimadura causada pela capsaicina. Quando aplicada na pele, promove uma resposta analgesica devido a dessensibilizaçao dos neuronios sensoriais causados pelo esgotamento da substancia P. A meia vida da capsaicina e vinte e quatro horas quando utilizada por via oral. Sua concentraçao maxima atinge o figado, rins e intestino ern uma hora apos administraçao oral. A capsaicina e principalmente eliminada pelos rins, com uma pequena proporçao nao transformada excretada nas fezes e na urina. Na aplicagao topica, a biotransformaçao da capsaicina foi considerada lenta e a maior parte da mesma permaneceu inalterada. A capsaicina e seus anélogos tem sido utilizados em cremes e patches para tratar sindromes de dor cronica como neuralgia pos-herpetica, dores musculoesqueleticas, neuropatia diabetica, osteoartrite e artrite reumatoide. A capsaicina tambem tem atividade antihiperlipidemica, propiedades anti-inflamatorias, antioxidantes e e efetiva no tratamento da dor associada com artrite e cistite. O capsiato, presente nas pimentas vermelhas nao pungentes tambem estimula o receptor TRPV1, sendo capaz de aumentar o metabolismo por estimulagao do sistema nervoso simpético, alem de ser provido de agao antiinflamatoria, porem por mecanismo ainda desconhecido (AU)

Las especies del género Capsicum, han sido estudiadas por los investigadores de todo el mundo. La pungencia es el principal atributo de los pimientos picantes y las sustancias responsables son los capsaicinoides. La capsaicina es la mas estudiada, su ruta biosintética es a través de la vía de fenilpropanoides y ácidos grasos. La capsaicina es un receptor TRPV1 agonista exógeno (receptor de potencial transitorio vaniloide tipo 1). El TRPV1 contiene una subunidad sensible al calor responsable de la sensación de ardor causada por la capsaicina. Cuando se aplica a la piel se promueve una respuesta analgésica debido a la desensibilización de las neuronas sensoriales causadas por el agotamiento de la sustancia P. La Vida media de la capsaicina es de 24 horas cuando se usa por via oral. Su distribución máxima alcanza el hígado, el riñón y el intestino en una hora después de la administración oral. La capsaicina se elimina principalmente por via renal, con una pequefia proporción no transformada excretada en las heces y en la orina. En la aplicación tópica de capsaicina la biotransformación se consideró lenta, y la mayor parte de la misma permaneció inalterada. La capsaicina y sus análogos han sido utilizados en cremas y apósitos para el tratamiento de síndromes de dolor crónico, tales como neuralgia postherpética, dolor musculo esquelético, neuropatía diabética, la osteoartritis y artritis reumatoide. La capsaicina también tiene actividad hipolipemiante, antiinflamatoria, antioxidante y es eficaz en el tratamiento del dolor asociado a artritis y cistitis. El capsiato, presente en pimientos rojos no picantes, también estimula el receptor TRPV1, siendo capaz de aumentar el metabolismo mediante la estimulación del sistema nervioso simpático, y presentando, además, acción antiinflamatoria, por un mecanismo aun desconocido (AU)

The species of the genus Capsicum have been studied by researchers worldwide. Pungency is the main attribute of peppers and it is due to the capsaicinoids. The most studied is capsaicin, biosynthetised through the phenylpropanoid and fatty acid pathway. Capsaicin is an exogenous agonist of TRPV1 receptor (transient receptor potential vanilloid type-1). The TRPV1 contains a subunit sensitive to heat, responsible for the burning sensation caused by capsaicin. When applied to the skin it promotes an analgesic response due to desensitization of sensory neurons caused by the depletion of substance P. The half-life of capsaicin is twenty-four hours when used orally. Its maximum concentration reaches the liver, kidney and intestine one hour after oral administration. Capsaicin is eliminated primarily by kidneys, with a small proportion of untransformed excreted in faeces and urine. After topical application, the biotransformation of capsaicin was considered slow, and it was mostly unchanged. Capsaicin and its analogues have been used in creams and patches to treat chronic pain syndromes, such as postherpetic neuralgia, musculoskeletal pain, diabetic neuropathy, osteoarthritis and rheumatoid arthritis. Capsaicin also has antihyperlipidemic, anti-inflammatory and antioxidant activities, being effective in the treatment of pain associated with arthritis and cystitis. The capsiate, present in non-pungent red peppers, also stimulates the TRPV1 receptor, being able to increase metabolism by stimulating the sympathetic nervous system, and showing, in addition, anti-inflammatory activity by a mechanism still unknown (AU)

Pungency of TRPV1 agonists is directly correlated with kinetics of receptor activation and lipophilicity.

TRPV1 (transient receptor potential vanilloid 1) is a ligand-gated ion channel expressed predominantly in nociceptive primary afferents that plays a key role in pain processing. In vivo activation of TRPV1 receptors by natural agonists like capsaicin is associated with a sharp and burning pain, frequently described as pungency. To elucidate the mechanisms underlying pungency we investigated a series of TRPV1 agonists that included both pungent and non-pungent compounds covering a large range of potencies. Pungency of capsaicin, piperine, arvanil, olvanil, RTX (resiniferatoxin) and SDZ-249665 was evaluated in vivo, by determining the increase in the number of eye wipes caused by direct instillation of agonist solutions into the eye. Agonist-induced calcium fluxes were recorded using the FLIPR technique in a recombinant, TRPV1-expressing cell line. Current-clamp recordings were performed in rat DRG (dorsal root ganglia) neurons in order to assess the consequences of TRPV1 activation on neuronal excitability. Using the eye wipe assay the following rank of pungency was obtained: capsaicin>piperine>RTX>arvanil>olvanil>SDZ-249665. We found a strong correlation between kinetics of calcium flux, pungency and lipophilicity of TRPV1 agonists. Current-clamp recordings confirmed that the rate of receptor activation translates in the ability of agonists to generate action potentials in sensory neurons. We have demonstrated that the lipophilicity of the compounds is directly related to the kinetics of TRPV1 activation and that the latter influences their ability to trigger action potentials in sensory neurons and, ultimately, pungency.

Arvanil inhibits T lymphocyte activation and ameliorates autoimmune encephalomyelitis.

This study examined the immunomodulatory effect of arvanil, a synthetic capsaicin-anandamide hybrid. Arvanil inhibits lymphocyte proliferation and IFN-gamma production. The phenotype of activated CD4+T cells treated with arvanil shows a down-regulation of T cell activation markers such as CD25, HLA-DR and CD134/OX40. Arvanil and anandamide do not induce apoptosis on CD4+T cells. Arvanil blocks the G1/S phase transition of the cell cycle in stimulated peripheral blood mononuclear cells, inducing activation of p21waf-1/cip-1 and phosphorylation of Akt/PKB. In vivo, arvanil ameliorates experimental autoimmune encephalomyelitis in the SJL/J mouse. Our findings have relevance for the use of arvanil and related compounds as a novel immunotherapeutic approach in the treatment of multiple sclerosis.

Cloning and pharmacological characterization of mouse TRPV1.

The Transient Receptor Potential cation channel V1 (TRPV1) is expressed in peripheral nociceptive neurons and is subject to polymodal activation via various agents including capsaicin, noxious heat, low extracellular pH, and direct phosphorylation by protein kinase C (PKC). We have cloned and heterologously expressed mouse TRPV1 (mTRPV1) and characterized its function utilizing FLIPR-based calcium imaging to measure functional responses to various small molecule agonists, low pH and direct phosphorylation via PKC. The various TRPV1 agonists activated mTRPV1 with a rank order of agonist potency of (resiniferatoxin (RTX) = arvanil > capsaicin = olvanil > OLDA > PPAHV) (EC50 values of 0.15+/-0.04 nM, 0.27+/-0.07 nM, 9.1+/-1.2 nM, 3.7+/-0.3 nM, 258+/-105 nM, and 667+/-151 nM, respectively). Additionally, mTRPV1 was activated by either low pH or with addition of the PKC activator phorbol 12-myristate 13-acetate (PMA). The TRPV1 antagonists iodinated-resiniferatoxin (I-RTX) or BCTC were both able to block capsaicin, pH and PKC-induced responses of mTRPV1 (IC50 (I-RTX) = 0.35+/-0.12 nM, 1.9+/-0.7 nM, and 0.80+/-0.68 nM, IC50 (BCTC) = 1.3+/-0.36 nM, 0.59+/-0.16 nM, and 0.37+/-0.15 nM, respectively). However, the antagonist capsazepine was only able to inhibit a capsaicin-evoked response of mTRPV1 with an IC50 of 1426+/-316 nM. Comparable results were achieved with rat TRPV1, while capsazepine blocked all modes of human TRPV1 activation. Thus, the mTRPV1 cation channel has a molecular pharmacological profile more akin to rat TRPV1 than either human or guinea pig TRPV1 and the molecular pharmacology suggests that capsazepine may be an ineffective TRPV1 antagonist for in vivo models of inflammatory pain in the mouse.

Noxious heat-induced CGRP release from rat sciatic nerve axons in vitro.

Noxious heat may act as an endogenous activator of the ionotropic capsaicin receptor (VR1) and of its recently found homologue VRL1, expressed in rat dorsal root ganglion cells and present along their nerve fibres. We have previously reported that capsaicin induces receptor-mediated and Ca++-dependent calcitonin gene-related peptide (CGRP) release from axons of the isolated rat sciatic nerve. Here we extended the investigation to noxious heat stimulation and the transduction mechanisms involved. Heat stimulation augmented the CGRP release from desheathed sciatic nerves in a log-linear manner with a Q10 of approximately 15 and a threshold between 40 and 42 degrees C. The increases were 1.75-fold at 42 degrees C, 3.8-fold at 45 degrees C and 29.1-fold at 52 degrees C; in Ca++-free solution these heat responses were abolished or reduced by 71 and 92%, respectively. Capsazepine (10 microm) and Ruthenium Red (1 microm) used as capsaicin receptor/channel antagonists did not significantly inhibit the heat-induced release. Pretreatment of the nerves with capsaicin (100 microm for 30 min) caused complete desensitization to 1 microm capsaicin, but a significant heat response remained, indicating that heat sensitivity is not restricted to capsaicin-sensitive fibres. The sciatic nerve axons responded to heat, potassium and capsaicin stimulation with a Ca++-dependent CGRP release. Blockade of the capsaicin receptor/channels had little effect on the heat-induced neuropeptide release. We conclude therefore that other heat-activated ion channels than VR1 and VRL1 in capsaicin-sensitive and -insensitive nerve fibres may cause excitation, axonal Ca++ influx and subsequent CGRP release.

Anandamide and methanandamide induce both vanilloid VR1- and cannabinoid CB1 receptor-mediated changes in heart rate and blood pressure in anaesthetized rats.

In anaesthetized rats activation of vanilloid receptors on sensory vagal nerves elicits rapid bradycardia and hypotension (Bezold-Jarisch reflex). Recent in vitro experiments revealed that the endogenous cannabinoid ligand anandamide acts as an agonist at the vanilloid VRI receptors. The present study was aimed at examining whether vanilloid VR1 receptors are involved in the cardiovascular effects of anandamide in the anaesthetized rat. Intravenous injection of anandamide, its stable analogue methanandamide and the vanilloid receptor agonist capsaicin produced a dose-dependent immediate and short-lasting decrease in heart rate and blood pressure with the following rank order of potencies: capsaicin > methanandamide > anandamide. This bradycardia was dose-dependently diminished by the selective vanilloid receptor antagonist capsazepine (0.3-3 micromol/kg) and the nonselective inhibitor of these receptors, ruthenium red (1-10 micromol/kg). Both antagonists reduced or tended to reduce the hypotension stimulated by the agonists. Following this bradycardia and hypotension (presumably evoked by the Bezold-Jarisch reflex; phase I), capsaicin, anandamide and methanandamide led to a brief vasopressor effect (phase II). Subsequently both anandamides, but not capsaicin, induced a more prolonged decrease in blood pressure (phase III). Capsazepine and ruthenium red (at doses up to 3 tmol/kg and 10 micromol/kg, respectively) failed to affect these changes in blood pressure. The cannabinoid CB1 receptor antagonist SR 141716 at 3 micromol/kg abolished the prolonged decrease in blood pressure (phase III) induced by anandamide and methanandamide, but had no effect on the reflex bradycardia and hypotension (phase I) and on the subsequent vasopressor effect (phase II) evoked by capsaicin, anandamide and methanandamide. In conclusion, the endogenous cannabinoid receptor agonist anandamide and its stable analogue methanandamide induce reflex bradycardia and hypotension (phase I) by activating the vanilloid VRI receptor. Whereas the mechanism underlying the brief vasopressor effect (phase II) is unknown, the prolonged hypotension (phase III) results from stimulation of the cannabinoid CB1 receptor.

Quantitative structure-agonist activity relationship of capsaicin analogues.

The MULTIple Computer Automated Structure Evaluation (MULTICASE) methodology has been used to study the quantitative structure-agonist activity relationship of a series of capsaicin agonists. A number of substructures and physiochemical properties of capsaicin analogues were identified as being responsible for high agonist potency. The optimal log P value for the agonist potency as estimated from QSAR analysis is 5.12. It was also found that a cluster of inactive molecules in the database have lipophilicity values below 2.94. Molecular modeling was employed to elucidate the detailed structural features of the pharmacophore of capsaicin analogues. Systematic conformational analysis has shown that the activity of capsaicin analogues strongly depends upon their ability to reach the required conformational profile. Based upon these observations, a three-dimensional pharmacophore model for the capsaicin-receptor interactions is proposed.

Protons: small stimulants of capsaicin-sensitive sensory nerves.

The data reviewed in this article suggest that protons should no longer be considered simply as an unwanted by-product of anaerobic respiration that results from either an accumulation of inflammatory cells or a reduced oxygenated blood supply during ischaemia. A fall in extracellular pH can stimulate a subpopulation of sensory nerves by activation of ion channels. The available evidence indicates that most, if not all, of the activated neurones are also stimulated by capsaicin, and that protons and capsaicin share a common mechanism of neuronal activation. A proton should be viewed as a mediator that elicits a protective response with reflex cardiovascular and respiratory responses, which modulate systemic blood flow, and with the local release of sensory neuropeptides, which vasodilates the microvasculature and stimulates extravasation.