Anti-obesity effect of intranasal administration of galanin-like peptide (GALP) in obese mice

Kageyama, Haruaki; Shiba, Kanako; Hirako, Satoshi; Wada, Nobuhiro; Yamanaka, Satoru; Nogi, Yukinori; Takenoya, Fumiko; Nonaka, Naoko; Hirano, Tsutomu; Inoue, Shuji; Shioda, Seiji

doi:10.1038/srep28200

Cited by 22 publications

(23 citation statements)

References 38 publications

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“…Thus, we examined whether SG2A can be delivered to the CNS by i.n. administration, a non-invasive route for enabling efficient crossing of the blood-brain barrier (Kageyama et al, 2016). Behavioral tests were performed 2–3 h after SG2A i.n.…”

Section: Resultsmentioning

confidence: 99%

“…The pharmacological relevance of SG2A is underscored by its biased agonism toward G-protein-dependent signaling over β-arrestin-mediated signaling, which is similar to SPX but different from GAL with unbiased activation (Reyes-Alcaraz et al, 2018). Probably due to β-arrestin-mediated signaling, classical agonists often result in contradictory results, such as with GAL for depression-like behaviors (Lu et al, 2005; Kuteeva et al, 2008) and the dichotomous action/dose-dependent inaction of galanin-like peptide in regulating food intake (Lawrence et al, 2002; Kageyama et al, 2016). By contrast, SG2A shows dose-dependent and consistent effects on mood and appetite behaviors during repetitive administrations.…”

Section: Discussionmentioning

confidence: 99%

“…A major challenge for treatments involving peptide drugs is bypassing the blood-brain barrier. Over the last several decades, diverse formulations and devices have been developed to transport the drugs from the nose directly to the brain, showing promise for therapeutic efficacy based on animal models and clinical trials in humans (Craft et al, 2012; Striepens et al, 2013; Kageyama et al, 2016). Notably, i.n.…”

Section: Discussionmentioning

confidence: 99%

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Spexin-Based Galanin Receptor Type 2 Agonist for Comorbid Mood Disorders and Abnormal Body Weight

et al. 2019

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Despite the established comorbidity between mood disorders and abnormal eating behaviors, the underlying molecular mechanism and therapeutics remain to be resolved. Here, we show that a spexin-based galanin receptor type 2 agonist (SG2A) simultaneously normalized mood behaviors and body weight in corticosterone pellet-implanted (CORTI) mice, which are underweight and exhibit signs of anhedonia, increased anxiety, and depression. Administration of SG2A into the lateral ventricle produced antidepressive and anxiolytic effects in CORTI mice. Additionally, SG2A led to a recovery of body weight in CORTI mice while it induced significant weight loss in normal mice. In Pavlovian fear-conditioned mice, SG2A decreased contextual and auditory fear memory consolidation but accelerated the extinction of acquired fear memory without altering innate fear and recognition memory. The main action sites of SG2A in the brain may include serotonergic neurons in the dorsal raphe nucleus for mood control, and proopiomelanocortin/corticotropin-releasing hormone neurons in the hypothalamus for appetite and body weight control. Furthermore, intranasal administration of SG2A exerted the same anxiolytic and antidepressant-like effects and decreased food intake and body weight in a dose-dependent manner. Altogether, these results indicate that SG2A holds promise as a clinical treatment for patients with comorbid mood disorders and abnormal appetite/body weight.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Spexin-Based Galanin Receptor Type 2 Agonist for Comorbid Mood Disorders and Abnormal Body Weight

et al. 2019

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“…Consequently, in our future studies, we will look for a safer administration route that is equally effective, such as intranasal injection, which has been shown to have positive effects when treating stroke patients with insulin and insulin growth factor 1 [ 38 ]. In addition, the intranasal administration method has also been shown to be effective when treating obese mice with GAL-like peptides [ 39 ]. Meanwhile, after 24 h of reperfusion, both GAL and GalR1 showed a significant increase in the ipsilateral versus contralateral cortex, suggesting GAL’s involvement in ischemic stroke.…”

Section: Discussionmentioning

confidence: 99%

Galanin Protects from Caspase-8/12-initiated Neuronal Apoptosis in the Ischemic Mouse Brain via GalR1

Zhu

Liu

et al. 2017

Aging and disease

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Galanin (GAL) plays key role in many pathophysiological processes, but its role in ischemic stroke remains unclear. Here, the models of 1 h middle cerebral artery occlusion (MCAO)/1-7 d reperfusion (R)-induced ischemic stroke and in vitro cell ischemia of 1 h oxygen-glucose deprivation (OGD)/24 h reoxygenation in primary cultured cortical neurons were used to explore GAL’s effects and its underlying mechanisms. The results showed significant increases of GAL protein levels in the peri-infarct region (P) and infarct core (I) within 48 h R of MCAO mice (p<0.001). The RT-qPCR results also demonstrated significant increases of GAL mRNA during 24-48 h R (p<0.001), and GAL receptors GalR1-2 (but not 3) mRNA levels in the P region at 24 h R of MCAO mice (p<0.001). Furthermore, the significant decrease of infarct volume (p<0.05) and improved neurological outcome (p<0.001-0.05) were observed in MCAO mice following 1 h pre- or 6 h post-treatment of GAL during 1-7 d reperfusion. GalR1 was confirmed as the receptor responsible for GAL-induced neuroprotection by using GalR2/3 agonist AR-M1896 and Lentivirus-based RNAi knockdown of GalR1. GAL treatment inhibited Caspase-3 activation through the upstream initiators Capsases-8/-12 (not Caspase-9) in both P region and OGD-treated cortical neurons. Meanwhile, GAL’s neuroprotective effect was not observed in cortical neurons from conventional protein kinase C (cPKC) γ knockout mice. These results suggested that exogenous GAL protects the brain from ischemic injury by inhibiting Capsase-8/12-initiated apoptosis, possibly mediated by GalR1 via the cPKCγ signaling pathway.

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“…GALP seems to be a promising peptide in the obesity treating. GALP administration has been eff ective in ameliorating the obesity in mice, where it has been shown that brain uptake of GALP is higher aft er intranasal than intravenous administration Kageyama et al 2016). Administration of GALP in mice, but not rats, resulted in an acute orexigenic eff ect that may be explained by an NPY input to GALP neurons from the ARC NPYcontaining neurons and orexin-containing neurons in LHA, in addition to fi bers that project from GALP neurons to orexin and melanin-concentrating hormone (MCH) ones in the LHA (Takenoya et al 2005).…”

Section: Th E Hypothalamus Role In the Food Intake Controlmentioning

confidence: 99%

Central and peripheral control of food intake

Abdalla

2017

Endocrine Regulations

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Th e maintenance of the body weight at a stable level is a major determinant in keeping the higher animals and mammals survive. Th e body weight depends on the balance between the energy intake and energy expenditure. Increased food intake over the energy expenditure of prolonged time period results in an obesity. Th e obesity has become an important worldwide health problem, even at low levels. Th e obesity has an evil eff ect on the health and is associated with a shorter life expectancy. A complex of central and peripheral physiological signals is involved in the control of the food intake. Centrally, the food intake is controlled by the hypothalamus, the brainstem, and endocannabinoids and peripherally by the satiety and adiposity signals. Comprehension of the signals that control food intake and energy balance may open a new therapeutic approaches directed against the obesity and its associated complications, as is the insulin resistance and others. In conclusion, the present review summarizes the current knowledge about the complex system of the peripheral and central regulatory mechanisms of food intake and their potential therapeutic implications in the treatment of obesity. Th e maintenance of the body weight at a stable level is a major determinant in keeping the higher animals and mammals survive (Jequier and Tappy 1999). As a compensatory mechanism, hunger increases and energy expenditure decreases the weight loss. However, opposite responses are triggered when body weight increases. Body weight can change only when energy intake is not equal to energy expenditure over a given period of time (Bray et al. 2012). A complex physiological control system is involved in the maintenance of the energy balance. Th is system includes aff erent signals from the periphery about the state of the energy stores and eff erent signals that affect the energy intake and expenditure (Sandoval et al. 2008). Th is regulatory system is formed by multiple interactions between the gastrointestinal tract (GIT), adipose tissue, and the central nervous system (CNS). It is infl uenced by behavioral, sensorial, autonomic, nutritional, and endocrine mechanisms (Boguszewski et al. 2010). Satiety and adiposity signalsTh e food intake control includes a short-term regulation, which determines the beginning and the end of a meal (hunger and satiation) and the interval between the meals (satiety) and a long-term regulation with factors (signals of adiposity), which help to regulate the body energy depots (Cummings and Overduin 2007).Th e satiation means a suppression of the hunger and termination of the food intake aft er ingestion of Unauthenticated Download Date | 5/11/18 9:54 AM

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Anti-obesity effect of intranasal administration of galanin-like peptide (GALP) in obese mice

Cited by 22 publications

References 38 publications

Spexin-Based Galanin Receptor Type 2 Agonist for Comorbid Mood Disorders and Abnormal Body Weight

Spexin-Based Galanin Receptor Type 2 Agonist for Comorbid Mood Disorders and Abnormal Body Weight

Galanin Protects from Caspase-8/12-initiated Neuronal Apoptosis in the Ischemic Mouse Brain via GalR1

Central and peripheral control of food intake

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