Glucagon-Like Peptide 1 Stimulates Hypothalamic Proopiomelanocortin Neurons

Ma, Xiaosong; Ashcroft, Frances M.

doi:10.1523/jneurosci.1025-07.2007

Cited by 60 publications

(40 citation statements)

References 37 publications

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“…GLP-1 is also synthesized in specific neuron populations in the nucleus of the solitary tract of the hindbrain (Han et al, 1986;Jin et al, 1988), and GLP-1 receptors are found in many CNS areas known to be involved in the control of energy metabolism (Larsen et al, 1997a,b;Merchenthaler et al, 1999), including the hypothalamic arcuate and paraventricular nuclei. Consistent with this, GLP-1 has been reported to directly stimulate hypothalamic neuroendocrine neurons including those expressing pro-opiomelanocortin (Larsen et al, 1997b;Ma et al, 2007). Biologically, GLP-1 exerts a broad range of actions such as stimulating insulin release, reducing glucagon release, and reducing gastric emptying (Willms et al, 1996;Baggio et al, 2004), and at least some of its actions appear to be mediated through neuroendocrine mechanisms.…”

Section: Introductionmentioning

confidence: 66%

Direct Control of Peripheral Lipid Deposition by CNS GLP-1 Receptor Signaling Is Mediated by the Sympathetic Nervous System and Blunted in Diet-Induced Obesity

Nogueiras¹,

Pérez-Tilve²,

et al. 2009

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We investigated a possible role of the central glucagon-like peptide (GLP-1) receptor system as an essential brain circuit regulating adiposity through effects on nutrient partitioning and lipid metabolism independent from feeding behavior. Both lean and diet-induced obesity mice were used for our experiments. GLP-1 (7-36) amide was infused in the brain for 2 or 7 d. The expression of key enzymes involved in lipid metabolism was measured by real-time PCR or Western blot. To test the hypothesis that the sympathetic nervous system may be responsible for informing adipocytes about changes in CNS GLP-1 tone, we have performed direct recording of sympathetic nerve activity combined with experiments in genetically manipulated mice lacking ␤-adrenergic receptors. Intracerebroventricular infusion of GLP-1 in mice directly and potently decreases lipid storage in white adipose tissue. These effects are independent from nutrient intake. Such CNS control of adipocyte metabolism was found to depend partially on a functional sympathetic nervous system. Furthermore, the effects of CNS GLP-1 on adipocyte metabolism were blunted in diet-induced obese mice. The CNS GLP-1 system decreases fat storage via direct modulation of adipocyte metabolism. This CNS GLP-1 control of adipocyte lipid metabolism appears to be mediated at least in part by the sympathetic nervous system and is independent of parallel changes in food intake and body weight. Importantly, the CNS GLP-1 system loses the capacity to modulate adipocyte metabolism in obese states, suggesting an obesity-induced adipocyte resistance to CNS GLP-1.

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Section: Introductionmentioning

confidence: 66%

Direct Control of Peripheral Lipid Deposition by CNS GLP-1 Receptor Signaling Is Mediated by the Sympathetic Nervous System and Blunted in Diet-Induced Obesity

Nogueiras¹,

Pérez-Tilve²,

et al. 2009

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“…It is well known that NTS catecholaminergic neurons project to the parvocellular subdivision of the PVN; therefore, ascending projections from NTS presumably could activate CRF neurons in the PVN (21). On the other hand, activation of ARC following a meal has been associated with direct actions of meal-related signals, such as GLP-1 and peptide YY (3,23).…”

Section: Discussionmentioning

confidence: 99%

Hypophagia induced by glucocorticoid deficiency is associated with an increased activation of satiety-related responses

Uchôa¹,

Sabino²,

Ruginsk³

et al. 2009

Journal of Applied Physiology

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Uchoa ET, Sabino HA, Ruginsk SG, Antunes-Rodrigues J, Elias LL. Hypophagia induced by glucocorticoid deficiency is associated with an increased activation of satiety-related responses. J Appl Physiol 106: 596 -604, 2009. First published November 20, 2008 doi:10.1152/japplphysiol.90865.2008.-Glucocorticoids have major effects on food intake, demonstrated by the decrease of food intake following adrenalectomy. Satiety signals are relayed to the nucleus of the solitary tract (NTS), which has reciprocal projections with the arcuate nucleus (ARC) and paraventricular nucleus (PVN) of the hypothalamus. We evaluated the effects of glucocorticoids on the activation of hypothalamic and NTS neurons induced by food intake in rats subjected to adrenalectomy (ADX) or sham surgery 7 days before the experiments. One-half of ADX animals received corticosterone (ADXϩB) in the drinking water (B: 25 mg/l). Fos/tyrosine hydroxylase (TH), Fos/corticotrophin-releasing factor (CRF) and Fos immunoreactivity were assessed in the NTS, PVN, and ARC, respectively. Food intake and body weight were reduced in the ADX group compared with sham and ADXϩB groups. Fos and Fos/TH in the NTS, Fos, and Fos/CRF immunoreactive neurons in the PVN and Fos in the ARC were increased after refeeding, with higher number in the ADX group, compared with sham and ADXϩB groups. CCK administration showed no hypophagic effect on ADX group despite a similar increase of Fos/TH immunoreactive neurons in the NTS compared with sham and ADXϩB groups, suggesting that CCK alone cannot further increase the anorexigenic effect induced by glucocorticoid deficiency. The present data indicate that glucocorticoid withdrawal reduced food intake, which was associated with higher activation of ARC, CRF neurons of the PVN, and catecholaminergic neurons of the NTS. In the absence of glucocorticoids, satiety signals elicited during a meal lead to an augmented activation of brain stem and hypothalamic pathways. glucocorticoids; food intake; satiety signals; nucleus of the solitary tract; paraventricular nucleus of the hypothalamus; arcuate nucleus of the hypothalamus GLUCOCORTICOIDS PLAY AN IMPORTANT ROLE in the control of feeding behavior. Increased food intake and body weight gain are associated with glucocorticoid treatment in humans (46). On the other hand, bilateral adrenalectomy (ADX) reduces food intake and body weight gain, and these effects are reversed by glucocorticoid replacement in rats (12). Furthermore, ADX reduces hyperphagia and obesity in different experimental models, whereas glucocorticoid replacement reverses these effects (4,8,52). Hypophagia induced by ADX has been associated with a decrease of mRNA expression of hypothalamic neuropeptide Y (NPY), a potent orexigenic neuropeptide (41). ADX also may reduce food intake through the increase of corticotrophin-releasing factor (CRF) mRNA expression in the paraventricular nucleus (PVN), since CRF is a well-known anorexigenic peptide (1, 2). CRF neurons in the PVN receive projections from neurons of the nucleus of the...

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“…Nonetheless, it is often asserted that hypothalamic/forebrain processing is critical for mediating the effects of peripheral GLP-1R stimulation as well as central activation. 11,[28][29][30][31][32] We review the results from experiments that used complete supracollicular transection of the rat brain to: (1) block the ascending projections to the hypothalamus and ventral forebrain that originate in the caudal brainstem; (2) remove descending projections from the hypothalamus and basal forebrain to hindbrain behavioral and autonomic effectors and thereby (3) eliminate forebrain-caudal brainstem communication. 33 This strategy was used to directly investigate the importance of hypothalamic/forebrain and caudal brainstem processing in the mediation of behavioral, sympathetic and parasympathetic responses generated by peripheral or central GLP-1R agonist treatment.…”

Section: Glp-1mentioning

confidence: 99%

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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Glucagon-Like Peptide 1 Stimulates Hypothalamic Proopiomelanocortin Neurons

Cited by 60 publications

References 37 publications

Direct Control of Peripheral Lipid Deposition by CNS GLP-1 Receptor Signaling Is Mediated by the Sympathetic Nervous System and Blunted in Diet-Induced Obesity

Direct Control of Peripheral Lipid Deposition by CNS GLP-1 Receptor Signaling Is Mediated by the Sympathetic Nervous System and Blunted in Diet-Induced Obesity

Hypophagia induced by glucocorticoid deficiency is associated with an increased activation of satiety-related responses

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

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