Dorsal Hindbrain 5′-Adenosine Monophosphate-Activated Protein Kinase as an Intracellular Mediator of Energy Balance

Hayes, Matthew R.; Skibicka, Karolina P.; Bence, Kendra K.; Grill, Harvey J.

doi:10.1210/en.2008-1319

Cited by 75 publications

(98 citation statements)

References 47 publications

(71 reference statements)

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“…Using western blots and activity assays we show that food deprivation elevates and refeeding reduces AMPK activity in NTS-enriched lysates. 62 Moreover, we show that the intake reduction resulting from hindbrain-directed leptin is reversed by hindbrain-directed treatment with AICA, an AMPmimicking promoter of AMPK activity. Our data are consistent with the hypothesis that the intake-inhibitory effect of leptin is mediated in part by the synergistic actions of leptin and GI vagal afferent signaling in medial NTS neurons, and that AMPK activity in these neurons may be a signal common to both effects.…”

Section: Glp-1mentioning

confidence: 79%

The nucleus tractus solitarius: a portal for visceral afferent signal processing, energy status assessment and integration of their combined effects on food intake

2009

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For humans and animal models alike there is general agreement that the central nervous system processing of gastrointestinal (GI) signals arising from ingested food provides the principal determinant of the size of meals and their frequency. Despite this, relatively few studies are aimed at delineating the brain circuits, neurochemical pathways and intracellular signals that mediate GI-stimulation-induced intake inhibition. Two additional motivations to pursue these circuits and signals have recently arisen. First, the success of gastric-bypass surgery in obesity treatment is highlighting roles for GI signals such as glucagon-like peptide-1 (GLP-1) in intake and energy balance control. Second, accumulating data suggest that the intakereducing effects of leptin may be mediated through an amplification of the intake-inhibitory effects of GI signals. Experiments reviewed show that: (1) the intake-suppressive effects of a peripherally administered GLP-1 receptor agonist is mediated by caudal brainstem neurons and that forebrain-hypothalamic neural processing is not necessary for this effect; (2) a population of medial nucleus tractus solitarius (NTS) neurons that are responsive to gastric distention is also driven by leptin; (3) caudal brainstem-targeted leptin amplifies the food-intake-inhibitory effects of gastric distention and intestinal nutrient stimulation; (4) adenosine monophosphate-activated protein kinase (AMPK) activity in NTS-enriched brain lysates is elevated by food deprivation and reduced by refeeding and (5) the intake-suppressive effect of hindbrain-directed leptin is reversed by elevating hindbrain AMPK activity. Overall, data support the view that the NTS and circuits within the hindbrain mediate the intake inhibition of GI signals, and that the effects of leptin on food intake result from the amplification of GI signal processing.

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Section: Glp-1mentioning

confidence: 79%

The nucleus tractus solitarius: a portal for visceral afferent signal processing, energy status assessment and integration of their combined effects on food intake

2009

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“…Food deprivation activates AMPK and food intake can be decreased or increased by drugs that enhance or block AMPK activation (13). Therefore, our previous studies of AMPK (25) are of interest in the present context.…”

Section: Discussionmentioning

confidence: 95%

Stimulation of feeding by three different glucose-sensing mechanisms requires hindbrain catecholamine neurons

Wang

Dinh

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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Li AJ, Wang Q, Dinh TT, Powers BR, Ritter S. Stimulation of feeding by three different glucose-sensing mechanisms requires hindbrain catecholamine neurons. Am J Physiol Regul Integr Comp Physiol 306: R257-R264, 2014. First published December 31, 2013 doi:10.1152/ajpregu.00451.2013-Previous work has shown that hindbrain catecholamine neurons are required components of the brain's glucoregulatory circuitry. However, the mechanisms and circuitry underlying their glucoregulatory functions are poorly understood. Here we examined three drugs, glucosamine (GcA), phloridzin (Phl) and 5-thio-D-glucose (5TG), that stimulate food intake but interfere in different ways with cellular glucose utilization or transport. We examined feeding and blood glucose responses to each drug in male rats previously injected into the hypothalamic paraventricular nucleus with anti-dopamine-␤-hydroxylase conjugated to saporin (DSAP), a retrogradely transported immunotoxin that selectively lesions noradrenergic and adrenergic neurons, or with unconjugated saporin (SAP) control. Our major findings were 1) that GcA, Phl, and 5TG all stimulated feeding in SAP controls whether injected into the lateral or fourth ventricle (LV or 4V), 2) that each drug's potency was similar for both LV and 4V injections, 3) that neither LV or 4V injection of these drugs evoked feeding in DSAP-lesioned rats, and 4) that only 5TG, which blocks glycolysis, stimulated a blood glucose response. The antagonist of the MEK/ERK signaling cascade, U0126, attenuated GcA-induced feeding, but not Phl-or 5TG-induced feeding. Thus GcA, Phl, and 5TG, although differing in mechanism and possibly activating different neural populations, stimulate feeding in a catecholamine-dependent manner. Although results do not exclude the possibility that catecholamine neurons possess glucose-sensing mechanisms responsive to all of these agents, currently available evidence favors the possibility that the feeding effects result from convergent neural circuits in which catecholamine neurons are a required component.glucosamine; phloridzin; 5-thio-D-glucose; catecholamine neurons; feeding HINDBRAIN CATECHOLAMINE NEURONS are required components of the brain's glucoregulatory circuitry. Pharmacological (29), chemical (26, 43), or immunotoxic (35, 40) disruption of these neurons impairs or abolishes key protective responses to glucose deficiency induced by hypoglycemic doses of insulin or by central or peripheral blockade of glycolysis using the antimetabolic glucose analogue 2-deoxy-D-glucose (2DG). Dissection of the hindbrain catecholamine system using the retrogradely transported immunotoxin anti-dopamine-␤-hydroxylase conjugated to saporin (DSAP) has revealed distinct responses to glucoprivation that are dependent on hypothalamically and spinally projecting norepinephrine (NE) and/or epinephrine (E) neurons. Specifically, some of those NE and E neurons with processes that innervate the medial hypothalamic region are required for feeding (35), corticosterone (40), and reproductive responses (15)...

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“…Leptin's effects on food intake are likely mediated through the integration of outputs from PI3K, STAT3, and ERK signaling pathways (55)(56)(57)(58)(59)(60). Whereas initial studies of the central regulation of food intake were focused on the hypothalamus, a growing body of evidence supports an important role for extrahypothalamic neuronal populations, most notably in the midbrain and brainstem, in mediating leptin's effects on feeding behaviors (reviewed in ref.…”

Section: Discussionmentioning

confidence: 99%

“…bolus of dextrose. Whole-blood glucose was assayed via tail nick at 15,30,45,60,90, and 120 minutes after injection.…”

Section: Generation Of Leprmentioning

confidence: 99%

Disruption of hypothalamic leptin signaling in mice leads to early-onset obesity, but physiological adaptations in mature animals stabilize adiposity levels

Ring

Zeltser²

2010

J. Clin. Invest.

100

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Distinct populations of leptin-sensing neurons in the hypothalamus, midbrain, and brainstem contribute to the regulation of energy homeostasis. To assess the requirement for leptin signaling in the hypothalamus, we crossed mice with a floxed leptin receptor allele (Lepr fl ) to mice transgenic for Nkx2.1-Cre, which drives Cre expression in the hypothalamus and not in more caudal brain regions, generating Lepr Nkx2.1 KO mice. From weaning, Lepr Nkx2.1 KO mice exhibited phenotypes similar to those observed in mice with global loss of leptin signaling (Lepr db/db mice), including increased weight gain and adiposity, hyperphagia, cold intolerance, and insulin resistance. However, after 8 weeks of age, Lepr Nkx2.1 KO mice maintained stable adiposity levels, whereas the body fat percentage of Lepr db/db animals continued to escalate. The divergence in the adiposity phenotypes of Lepr db/db and Lepr Nkx2.1 KO mice with age was concomitant with increased rates of linear growth and energy expenditure in Lepr Nkx2.1 KO mice. These data suggest that remaining leptin signals in Lepr Nkx2.1 KO mice mediate physiological adaptations that prevent the escalation of the adiposity phenotype in adult mice. The persistence of severe adiposity in Lepr Nkx2.1 KO mice, however, suggests that compensatory actions of circuits regulating growth and energy expenditure are not sufficient to reverse obesity established at an early age. IntroductionGiven the increased worldwide prevalence of obesity and associated chronic diseases, understanding the cellular and molecular mechanisms regulating food intake, body composition, and energy expenditure have become a research priority (1, 2). The discovery of leptin, an adipokine (3) that circulates in levels proportional to fat stores (4), and its receptor (encoded by Lepr; refs. 5, 6) initiated a fundamental change in the way scientists view the circuits regulating energy homeostasis. Analyses of mice lacking leptin (Lep ob/ob ) and Lepr (Lepr db/db ) provided evidence that leptin signaling influences a wide range of phenotypes related to energy balance, including food intake, body composition, glucose homeostasis, metabolic rate, and thermoregulation (7-10). Cells in the CNS expressing the long isoform of Lepr (Lepr-b) have been shown to mediate most of leptin's effects on energy balance (11)(12)(13)(14).The highest levels of Lepr-b expression are found in the mediobasal hypothalamus (15,16). This finding, together with the observations that physical or chemical ablation of neurons in the hypothalamus resulted in severe dysregulation of food intake and body composition (17)(18)(19)(20), led many to hypothesize that the hypothalamus is the principal site of leptin-mediated regulation of phenotypes related to energy homeostasis. Moreover, localized restoration of Lepr-b expression in the arcuate nucleus of the hypothalamus (ARH) ameliorates many of the metabolic phenotypes of Lepr db/db mice (21,22). Conversely, the selective loss of Lepr-b signaling in subpopulations of neurons in the ARH or vent...

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Dorsal Hindbrain 5′-Adenosine Monophosphate-Activated Protein Kinase as an Intracellular Mediator of Energy Balance

Cited by 75 publications

References 47 publications

The nucleus tractus solitarius: a portal for visceral afferent signal processing, energy status assessment and integration of their combined effects on food intake

The nucleus tractus solitarius: a portal for visceral afferent signal processing, energy status assessment and integration of their combined effects on food intake

Stimulation of feeding by three different glucose-sensing mechanisms requires hindbrain catecholamine neurons

Disruption of hypothalamic leptin signaling in mice leads to early-onset obesity, but physiological adaptations in mature animals stabilize adiposity levels

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