Effects of glucagon-like peptide 1 and oxyntomodulin on neuronal activity of ghrelin-sensitive neurons in the hypothalamic arcuate nucleus

Riediger, Thomas; Eisele, Nicole; Scheel, Caroline; Lutz, Thomas

doi:10.1152/ajpregu.00438.2009

Cited by 26 publications

(14 citation statements)

References 41 publications

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“…The effects of GLP-1 and OXM on neuronal activity in the ARC are similar. In rats, both hormones induced excitatory responses in ghrelin-inhibited cells (67) (see example in Fig. 2) suggesting a stimulation of POMC signalling, which is consistent with the high expression of the GLP-1R in POMC neurons (65) .…”

Section: Peptide Yy/glucagon-like Peptidesupporting

confidence: 77%

The receptive function of hypothalamic and brainstem centres to hormonal and nutrient signals affecting energy balance

Riediger

2012

Proc. Nutr. Soc.

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The hypothalamic arcuate nucleus (ARC) and the area postrema (AP) represent targets for hormonal and metabolic signals involved in energy homoeostasis, e.g. glucose, amylin, insulin, leptin, peptide YY (PYY), glucagon-like peptide 1 (GLP-1) and ghrelin. Orexigenic neuropeptide Y expressing ARC neurons are activated by food deprivation and inhibited by feeding in a nutrient-dependent manner. PYY and leptin also reverse or prevent fasting-induced activation of the ARC. Interestingly, hypothalamic responses to fasting are blunted in different models of obesity (e.g. diet-induced obesity (DIO) or late-onset obesity). The AP also responds to feeding-related signals. The pancreatic hormone amylin acts via the AP to control energy intake. Amylin-sensitive AP neurons are also glucose-responsive. Furthermore, diet-derived protein attenuates amylin responsiveness suggesting a modulation of AP sensitivity by macronutrient supply. This review gives an overview of the receptive function of the ARC and the AP to hormonal and nutritional stimuli involved in the control of energy balance and the possible implications in the context of obesity. Collectively, there is consistency between the neurophysiological actions of these stimuli and their effects on energy homoeostasis under experimental conditions. However, surprisingly little progress has been made in the development of effective pharmacological approaches against obesity. A promising way to improve effectiveness involves combination treatments (e.g. amylin/leptin agonists). Hormonal alterations (e.g. GLP-1 and PYY) are also considered to mediate body weight loss observed in obese patients receiving bariatric surgery. The effects of hormonal and nutritional signals and their interactions might hold the potential to develop poly-mechanistic therapeutic strategies against obesity. Arcuate nucleus: Area postrema: Food intake: ObesityDriven by the search for therapeutic treatment strategies against obesity and associated metabolic disorders, considerable knowledge has accumulated about the control mechanisms involved in the maintenance of energy balance. The redundancy of control mechanisms, the capacity of these systems to compensate for pharmacological effects and the existence of obesity-related hormonal insensitivities make it difficult to achieve sufficient therapeutic efficiency for the reduction of body weight over longer periods of time. Evidently, at least under nonlaboratory conditions, so-called non-homoeostatic factors (hedonic properties and availability of food, food preferences, social factors, eating habits, etc.) and central reward mechanisms override homoeostatic hormonal and metabolic signals that are considered to reflect and to control the body's energy status.

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Section: Peptide Yy/glucagon-like Peptidesupporting

confidence: 77%

The receptive function of hypothalamic and brainstem centres to hormonal and nutrient signals affecting energy balance

Riediger

2012

Proc. Nutr. Soc.

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“…A suggested role for central GLP1-R signaling pathways in body energy balance (Tang-Christensen et al 2001; Hayes 2012; Meeran et al 1999; vanDijk and Thiele 1999) also is supported by evidence in rats and mice implicating central GLP1 in temperature regulation (Rinaman and Comer 2000; O’Shea et al 1996) and glucose homeostasis (Sandoval et al 2008). GLP1-R agonists enhance both excitatory and inhibitory synaptic inputs to identified neurons through presynaptic stimulation of transmitter release from axon terminals (Wan et al 2007; Acuna-Goycolea and van den Pol 2004), and postsynaptic effects of GLP1 on neuronal activity also are reported (Acuna-Goycolea and van den Pol 2004; Riediger et al 2010; Hayes 2012). Neuroanatomical results from the present study significantly expand current knowledge regarding the signaling capacity of GLP1 neurons by demonstrating that these neurons are glutamatergic, at least in rats, similar to other neuronal populations that use glutamate as a co-transmitter and/or as a synergistic enhancer of vesicular packaging and release (El Mestikawy et al 2011).…”

Section: Discussionmentioning

confidence: 99%

Glutamatergic phenotype of glucagon-like peptide 1 neurons in the caudal nucleus of the solitary tract in rats

et al. 2014

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The expression of a vesicular glutamate transporter (VGLUT) suffices to assign a glutamatergic phenotype to neurons and other secretory cells. For example, intestinal L cells express VGLUT2 and secrete glutamate along with glucagon-like peptide 1 (GLP1). We hypothesized that GLP1-positive neurons within the caudal (visceral) nucleus of the solitary tract (cNST) also are glutamatergic. To test this, the axonal projections of GLP1 and other neurons within the cNST were labeled in rats via iontophoretic delivery of anterograde tracer. Dual immunofluorescence and confocal microscopy was used to visualize tracer-, GLP1-, and VGLUT2-positive fibers within brainstem, hypothalamic, and limbic forebrain nuclei that receive input from the cNST. Electron microscopy was used to confirm GLP1 and VGLUT2 immunolabeling within the same axon varicosities, and fluorescent in situ hybridization was used to examine VGLUT2 mRNA expression by GLP1-positive neurons. Most anterograde tracer-labeled fibers displayed VGLUT2-positive varicosities, providing new evidence that ascending axonal projections from the cNST are primarily glutamatergic. Virtually all GLP1-positive varicosities also were VGLUT2-positive. Electron microscopy confirmed the colocalization of GLP1 and VGLUT2 immunolabeling in axon terminals that formed asymmetric (excitatory-type) synapses with unlabeled dendrites in the hypothalamus. Finally, in situ hybridization confirmed that GLP1-positive cNST neurons express VGLUT2 mRNA. Thus, hindbrain GLP1 neurons in rats are equipped to store glutamate in synaptic vesicles, and likely co-release both glutamate and GLP1 from axon varicosities and terminals in the hypothalamus and other brain regions.

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“…Furthermore, GLP-1 inhibits ghrelin-stimulated neuronal activity in the hypothalamus as well as its effects on food intake (34). Therefore, we next examined whether SIRT1 or p53 might be relevant for the central actions of liraglutide.…”

Section: Ampk Within the Vmh Is Essential For The Central Actions Of mentioning

confidence: 99%

GLP-1 Agonism Stimulates Brown Adipose Tissue Thermogenesis and Browning Through Hypothalamic AMPK

et al. 2014

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GLP-1 receptor (GLP-1R) is widely located throughout the brain, but the precise molecular mechanisms mediating the actions of GLP-1 and its long-acting analogs on adipose tissue as well as the brain areas responsible for these interactions remain largely unknown. We found that central injection of a clinically used GLP-1R agonist, liraglutide, in mice stimulates brown adipose tissue (BAT) thermogenesis and adipocyte browning independent of nutrient intake. The mechanism controlling these actions is located in the hypothalamic ventromedial nucleus (VMH), and the activation of AMPK in this area is sufficient to blunt both central liraglutide-induced thermogenesis and adipocyte browning. The decreased body weight caused by the central injection of liraglutide in other hypothalamic sites was sufficiently explained by the suppression of food intake. In a longitudinal study involving obese type 2 diabetic patients treated for 1 year with GLP-1R agonists, both exenatide and liraglutide increased energy expenditure. Although the results do not exclude the possibility that extrahypothalamic areas are also modulating the effects of GLP-1R agonists, the data indicate that long-acting GLP-1R agonists influence body weight by regulating either food intake or energy expenditure through various hypothalamic sites and that these mechanisms might be clinically relevant.

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Effects of glucagon-like peptide 1 and oxyntomodulin on neuronal activity of ghrelin-sensitive neurons in the hypothalamic arcuate nucleus

Cited by 26 publications

References 41 publications

The receptive function of hypothalamic and brainstem centres to hormonal and nutrient signals affecting energy balance

The receptive function of hypothalamic and brainstem centres to hormonal and nutrient signals affecting energy balance

Glutamatergic phenotype of glucagon-like peptide 1 neurons in the caudal nucleus of the solitary tract in rats

GLP-1 Agonism Stimulates Brown Adipose Tissue Thermogenesis and Browning Through Hypothalamic AMPK

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