In Vivo Evidence for Inverse Agonism of Agouti-Related Peptide in the Central Nervous System of Proopiomelanocortin-Deficient Mice
ABSTRACT Melanocyte-stimulating hormone (MSH) peptides processed from proopiomelanocortin (POMC) regulate energy homeostasis by activating neuronal melanocortin receptor (MC-R) signaling. Agouti-related peptide (AgRP) is a naturally occurring MC-R antagonist but also displays inverse agonism at constitutively active melanocortin-4 receptor (MC4-R) expressed on transfected cells. We investigated whether AgRP functions similarly in vivo using mouse models that lack all neuronal MSH, thereby precluding competitive antagonism of MC-R by AgRP.
Feeding and metabolic effects of the MC-R agonist melanotan II (MTII), AgRP, and ghrelin were investigated after intracerebroventricular injection in neural-specific POMC-deficient (Pomc(-/-)Tg/+) and global POMC-deficient (Pomc(-/-)) mice. Gene expression was quantified by RT-PCR.
Hyperphagic POMC-deficient mice were more sensitive than wild-type mice to the anorectic effects of MTII. Hypothalamic melanocortin-3 (MC3)/4-R mRNAs in POMC-deficient mice were unchanged, suggesting increased receptor sensitivity as a possible mechanism for the heightened anorexia. AgRP reversed MTII-induced anorexia in both mutant strains, demonstrating its ability to antagonize MSH agonists at central MC3/4-R, but did not produce an acute orexigenic response by itself. The action of ghrelin was attenuated in Pomc(-/-)Tg/+ mice, suggesting decreased sensitivity to additional orexigenic signals. However, AgRP induced delayed and long-lasting modifications of energy balance in Pomc(-/-)Tg/+, but not glucocorticoid-deficient Pomc(-/-) mice, by decreasing oxygen consumption, increasing the respiratory exchange ratio, and increasing food intake.
These data demonstrate that AgRP can modulate energy balance via a mechanism independent of MSH and MC3/4-R competitive antagonism, consistent with either inverse agonist activity at MC-R or interaction with a distinct receptor.
- SourceAvailable from: Marc Schneeberger
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- "contrasting actions of a-MSH and AGRP peptides on MCRs: while a-MSH is an endogenous MCR agonist, AGRP is an inverse agonist (Haskell-Luevano & Monck 2001, Nijenhuis et al. 2001, Tolle & Low 2008). Indeed, substantial experimental evidence indicates that the agonism of MCRs attenuates appetite and enhances energy expenditure, whereas their antagonism has essentially the opposite effects (Fan et al. 1997, Harrold et al. 1999, Hwa et al. 2001). "
ABSTRACT: Alterations in adequate energy balance maintenance results in serious metabolic disturbances such as obesity. In mammals, this complex process is orchestrated by multiple and distributed neuronal circuits. Hypothalamic and brainstem neurocircuitries are critically implicated in the sensing of circulating and local factors informing about the energy status of the organism. The integration of these signals culminates in the generation of specific and coordinated physiological responses aimed to regulate energy balance through the modulation of appetite and energy expenditure. In this article we review current knowledge on the homeostatic regulation of energy balance, emphasizing recent advances in mouse genetics, electrophysioly and optogenetic techniques that have greatly contributed to improve our understanding of this central process.Journal of Endocrinology 11/2013; 220(2). DOI:10.1530/JOE-13-0398 · 3.59 Impact Factor
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- "In addition to its action as a natural MC3R and MC4R antagonist, AgRP was shown to display inverse agonism in in vitro systems expressing constitutively active MC4R  . This finding was later confirmed in vivo in the Pomc À / À mouse . The MC4R is coupled to adenlyate cyclase and acts via mobilizing intracellular calcium . "
ABSTRACT: Obesity is characterized as an excess accumulation of body fat resulting from a positive energy balance. It is the major risk factor for type 2 diabetes (T2D). The evidence for familial aggregation of obesity and its associated metabolic diseases is substantial. To date, about 150 genetic loci identified in genome-wide association studies (GWAS) are linked with obesity and T2D, each accounting for only a small proportion of the predicted heritability. However, the percentage of overall trait variance explained by these associated loci is modest (~5-10% for T2D, ~2% for BMI). The lack of powerful genetic associations suggests that heritability is not entirely attributable to gene variations. Some of the familial aggregation as well as many of the effects of environmental exposures, may reflect epigenetic processes. This review summarizes our current knowledge on the genetic basis to individual risk of obesity and T2D, and explores the potential role of epigenetic contribution.11/2013; 2(4):337-347. DOI:10.1016/j.molmet.2013.09.002
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- "Arc NPY Signaling Controls POMC and GAD65 but Not AGRP Expression Having demonstrated the clear link between Arc NPY and energy expenditure and BAT thermogenesis, we next attempted to dissect the neuronal pathways and circuits initiated by Arcspecific NPY signaling. First, we assessed how increased Arc NPY signaling affects the expression levels of other known regulators of energy balance such as POMC and AGRP (Mountjoy, 2010; Ollmann et al., 1997; Tolle and Low, 2008) using in situ hybridization. Unilateral injection of the respective AAV vectors was chosen because it allowed us to use the contralateral side as an internal control. "
ABSTRACT: Neuropepetide Y (NPY) is best known for its powerful stimulation of food intake and its effects on reducing energy expenditure. However, the pathways involved and the regulatory mechanisms behind this are not well understood. Here we demonstrate that NPY derived from the arcuate nucleus (Arc) is critical for the control of sympathetic outflow and brown adipose tissue (BAT) function. Mechanistically, a key change induced by Arc NPY signaling is a marked Y1 receptor-mediated reduction in tyrosine hydroxylase (TH) expression in the hypothalamic paraventricular nucleus (PVN), which is also associated with a reduction in TH expression in the locus coeruleus (LC) and other regions in the brainstem. Consistent with this, Arc NPY signaling decreased sympathetically innervated BAT thermogenesis, involving the downregulation of uncoupling protein 1 (UCP1) expression in BAT. Taken together, these data reveal a powerful Arc-NPY-regulated neuronal circuit that controls BAT thermogenesis and sympathetic output via TH neurons.Cell metabolism 02/2013; 17(2):236-48. DOI:10.1016/j.cmet.2013.01.006 · 16.75 Impact Factor