Alpha and beta‐adrenergic mediation of membrane potential changes and metabolism in rat brown adipose tissue.

Girardier, L; Schneider-Picard, Gisela

doi:10.1113/jphysiol.1983.sp014555

Cited by 38 publications

(38 citation statements)

References 18 publications

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“…7). Membrane depolarization in BAT has been previously shown to accompany thermogenesis (28,(42)(43)(44). Thus, the metabolic changes may, at least in part, occur via direct blockade of Kv1.3 channels in BAT.…”

Section: Resultsmentioning

confidence: 97%

“…The molecular mechanism responsible for these robust metabolic changes in BAT is unclear at this time, but may involve direct blockade of Kv1.3 channels that are expressed in BAT in mice on the obesity diet. Channel blockade would result in membrane depolarization and mimic the membrane-depolarizing effects of high external potassium concentrations that augment BAT thermogenesis (28,(42)(43)(44). However, tetraethylammonium at a dose that blocks Kv1.3 channels was reported not to alter norepinephrine-dependent thermogenesis (37).…”

Section: Discussionmentioning

confidence: 99%

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Selective Kv1.3 channel blocker as therapeutic for obesity and insulin resistance

Upadhyay¹,

Eckel‐Mahan²,

Mirbolooki³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Obesity is an epidemic, calling for innovative and reliable pharmacological strategies. Here, we show that ShK-186, a selective and potent blocker of the voltage-gated Kv1.3 channel, counteracts the negative effects of increased caloric intake in mice fed a diet rich in fat and fructose. ShK-186 reduced weight gain, adiposity, and fatty liver; decreased blood levels of cholesterol, sugar, HbA1c, insulin, and leptin; and enhanced peripheral insulin sensitivity. These changes mimic the effects of Kv1.3 gene deletion. ShK-186 did not alter weight gain in mice on a chow diet, suggesting that the obesityinducing diet enhances sensitivity to Kv1.3 blockade. Several mechanisms may contribute to the therapeutic benefits of ShK-186. ShK-186 therapy activated brown adipose tissue as evidenced by a doubling of glucose uptake, and increased β-oxidation of fatty acids, glycolysis, fatty acid synthesis, and uncoupling protein 1 expression. Activation of brown adipose tissue manifested as augmented oxygen consumption and energy expenditure, with no change in caloric intake, locomotor activity, or thyroid hormone levels. The obesity diet induced Kv1.3 expression in the liver, and ShK-186 caused profound alterations in energy and lipid metabolism in the liver. This action on the liver may underlie the differential effectiveness of ShK-186 in mice fed a chow vs. an obesity diet. Our results highlight the potential use of Kv1.3 blockers for the treatment of obesity and insulin resistance.

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Section: Resultsmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Selective Kv1.3 channel blocker as therapeutic for obesity and insulin resistance

Upadhyay¹,

Eckel‐Mahan²,

Mirbolooki³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Changes in membrane potential are the first measurable effects of hormonal stimulation in brown fat, but the roles of the electrical responses are not known. Norepinephrine (NE) applied either in vivo (Horwitz and Hamilton, 1984) or in vitro (Girardier, Seydoux, and Clausen, 1968;Girardier and Schneider-Picard, 1983;Schneider-Picard, Coles, and Girardier, 1985) induces a complex membrane potential response, consisting of a rapid depolarization and hyperpolarization, followed by a sustained depolarization. The initial depolarization and hyperpolarization are mediated by 0t-adrenergic receptors and precede any metabolic activation of the tissue.…”

Section: Introductionmentioning

confidence: 99%

Alpha-adrenergic stimulation activates a calcium-sensitive chloride current in brown fat cells.

Pappone

Lee

1995

The Journal of General Physiology

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The first response of brown adipocytes to adrenergic stimulation is a rapid depolarizing conductance increase mediated by 0t-adrenergic receptors. We used patch recording techniques on cultured brown fat cells from neonatal rats to characterize this conductance. Measurements in perforated patch clamped cells showed that fast depolarizing responses were frequent in cells maintained in culture for 1 d or less, but were seen less often in cells cultured for longer periods. Ion substitution showed that the depolarization was due to a selective increase in membrane chloride permeability. The reversal potential for the depolarizing current in perforated patch clamped cells indicated that intracellular chloride concentrations were significandy higher than expected if chloride were passively distributed. The chloride conductance could be activated by increases in intracellular calcium, either by exposing intact cells to the ionophore A23187 or by using pipette solutions with free calcium levels of 0.2-1.0 I~M in whole-cell configuration. The chloride conductance did not increase monotonically with increases in intracellular calcium, and going whole cell with pipette-free calcium concentrations ~>10 ~M rapidly inactivated the current. The chloride currents ran down in whole-cell recordings using intracellular solutions of various compositions, and were absent in excised patches. These findings imply that cytoplasmic factors in addition to intracellular calcium are involved in regulation of the chloride conductance. The chloride currents could be blocked by niflumic acid or flufenamic acid with ICs0s of 3 and 7 t~M, or by higher concentrations of SITS (ICs0 = 170 o~M), DIDS (Its0 = 50 I~M), or 9-anthracene carboxylic acid (ICs0 = 80 I~M). The chloride conductance activated in whole cell by intracellular calcium had the permeability sequence PNo3 >PI >PBr >Po >> P~,par~te, measured from either reversal potentials or conductances. Instantaneous current-voltage relations for the calcium-activated chloride currents were linear in symmetric chloride solutions. Much of the current was time and voltage independent and active at all membrane potentials between -100 and +100 mV, but an additional component of variable amplitude showed time-dependent activation with depolarization. Volume-sensitive chloride currents were also present in brown fat cells, but differed from the calcium-activated currents in that they responded to cell swelling, reAddress correspondence to Dr. Pamela Pappone, Division of Biological Sciences, Section of Neurobiology, Physiology, and Behavior, University of California, Davis, CA 95616. 232 THE JOURNAL OF GENERAL PHYSIOLOGY 9 VOLUME 106 9 1995 quired intracellular ATP in whole-cell recordings, showed no sensitivity to intracellular or extracellular calcium levels, and were relatively resistant to block by niflumic and flufenamic acids. We conclude that the intracellular calcium increases resulting from adrenergic stimulation in brown fat activate a chloride-selective membrane conductance distinct...

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“…For instance, neurally evoked metabolic events that do not depend on measurable changes in membrane potential have recently been suggested in brown adipose tissue (Girardier and Schneider-Picard 1983). It is also possible, in analogy to the LHRH system in sympathetic ganglia, that even though an SP-like substance is in terminals apposed to parasympathetic neurons, these neurons are not the physiological target for the peptide.…”

Section: Actions Of Sp On Mast Cellsmentioning

confidence: 98%

Peptides in Neuronal Function: Studies Using Frog Autonomic Ganglia

Jan¹,

Bowers²,

Branton³

et al. 1983

Cold Spring Harbor Symposia on Quantitative Biology

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At present, more than 20 peptides are considered as putative neurotransmitters, based primarily on their localization in nerve terminals and their actions on nerve cells (H6kfelt et al. 1980). The list is almost certainly not exhaustive and it is likely that more will be found in the future. If many peptides turn out to be neurotransmitters, one might wonder why the nervous system utilizes so many different transmitters. A detailed analysis of the action of a number of neuropeptides may reveal characteristics unique to peptidergic transmission and thus shed light on the functional significance of peptide transmitters and perhaps explain the need for multiple transmitters.Frog sympathetic ganglia and parasympathetic cardiac ganglia are excellent preparations for this purpose (Langley and Orbeli 1910; McMahan and Kuffler 1971). Structurally, they are very simple. Neurons in these ganglia are unipolar and have no dendrites. Preganglionic fibers make synaptic contacts almost exclusively on the ganglionic cell bodies. This arrangement facilitates analysis of the physiological effects of neurotransmitters and allows accurate anatomical description of synaptic connections. Analysis of possible actions of peptides in these two preparations has already revealed interesting features. In the frog sympathetic ganglia, a luteinizing hormone releasing hormone (LHRH)-Iike peptide is almost certain to be the transmitter that mediates a slow excitatory postsynaptic potential, the late slow EPSP. Certain properties of this peptidergic transmission appear to be strikingly different from those of conventional cholinergic transmission. For instance, although the LHRH-like peptide and acetylcholine (ACh) seem to be released from the same nerve terminals that form synapses of conventional morphology, the peptide can diffuse far greater distances than ACh and activate sympathetic neurons nonsynaptically. In the frog heart septum, all of the terminals on the parasympathetic neurons are positively stained by antibodies to substance P (SP). However, little or no electrical effects on those neurons have been detected that may be attributed to the SP-like immunoreactivity.Our preliminary results indicate that one target of the SP-like material may be the mast cells situated near the neurons. These results prompted us to propose a hypothesis about the general mode of actions of neuropeptides and to suggest why the nervous system uses so many different chemical messengers. METHODSBoth preparations used here, the paravertebral sympathetic ganglia and the parasympathetic ganglia of the interartrial septum of the heart, were isolated from bullfrogs (Rana catesbiana) as previously described (McMahan and Kuffler 1971;Jan and Jan 1982).Electrophysiological experiments. The isolated ganglia were pinned to a thin layer of Sylgard in a petri dish and viewed with Nomarski optics. The bath was continuously perfused at room temperature with Ringer's solution containing 115 mM NaCI, 2 mM KCI, 3.6 mM CaCI2, and 5 mM HEPES (pH 7.2). Conventional recording t...

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Alpha and beta‐adrenergic mediation of membrane potential changes and metabolism in rat brown adipose tissue.

Cited by 38 publications

References 18 publications

Selective Kv1.3 channel blocker as therapeutic for obesity and insulin resistance

Selective Kv1.3 channel blocker as therapeutic for obesity and insulin resistance

Alpha-adrenergic stimulation activates a calcium-sensitive chloride current in brown fat cells.

Peptides in Neuronal Function: Studies Using Frog Autonomic Ganglia

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