Hypothalamic AgRP neurons exert top-down control on systemic TNF-α release during endotoxemia

Boudjadja, Mehdi Boutagouga; Culotta, Isabella; Paula, Gabriela C. De; Harno, Erika; Hunter, Jenna; Cavalcanti-de-Albuquerque, J.P.; Luckman, Simon M.; Hepworth, Matthew R.; White, Anne; Aviello, Gabriella; D’Agostino, Giuseppe

doi:10.1016/j.cub.2022.09.017

Cited by 4 publications

(5 citation statements)

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“…For cerebrospinal fluid, we found that upregulated AGRP and FRZB, downregulated CTSF increased BD risk. AGRP, a biased agonist of melanocortin receptors coexpressed with neuropeptide Y and gamma-aminobutyric acid (GABA) in the hypothalamus, mediates neuroendocrine responses to immune (Boutagouga Boudjadja et al, 2022) and inflammatory regulation (Klima et al, 2023;Xiao, Xia-Zhang, Vulliemoz, Ferin, & Wardlaw, 2003) by AGRP neurons. A previous case-control study reported that AGRP levels were higher in euthymic bipolar disorder patients than in healthy controls (Özkorumak Karagüzel et al, 2018), which is consistent with our findings.…”

Section: Discussionmentioning

confidence: 99%

Uncovering novel drug targets for bipolar disorder: a Mendelian randomization analysis of brain, cerebrospinal fluid, and plasma proteomes

Jia,

Liu,

et al. 2024

Psychol. Med.

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Background There is a clear demand for innovative therapeutics for bipolar disorder (BD). Methods We integrated the largest BD genome-wide association study (GWAS) dataset (NCase = 41 917, NControl = 371 549) with protein quantitative trait loci from brain, cerebrospinal fluid, and plasma. Using a range of integrative analyses, including Mendelian randomization (MR), Steiger filter analysis, Bayesian colocalization, and phenome-wide MR analysis, we prioritized novel drug targets for BD. Additionally, we incorporated data from the UK Biobank (NCase = 1064, NControl = 365 476) and the FinnGen study (NCase = 7006, NControl = 329 192) for robust biological validation. Results Through MR analysis, we found that in the brain, downregulation of DNM3, MCTP1, ABCB8 and elevation of DFNA5 and PDF were risk factors for BD. In cerebrospinal fluid, increased BD risk was associated with increased levels of FRZB, AGRP, and IL36A and decreased CTSF and LRP8. Plasma analysis revealed that decreased LMAN2L, CX3CL1, PI3, NCAM1, and TIMP4 correlated with increased BD risk, but ITIH1 did not. All these proteins passed Steiger filtering, and Bayesian colocalization confirmed that 12 proteins were colocalized with BD. Phenome-wide MR analysis revealed no significant side effects for potential drug targets, except for LRP8. External validation further underscored the concordance between the primary and validation cohorts, confirming MCTP1, DNM3, PDF, CTSF, AGRP, FRZB, LMAN2L, NCAM1, and TIMP4 are intriguing targets for BD. Conclusions Our study identified druggable proteins for BD, including MCTP1, DNM3, and PDF in the brain; CTSF, AGRP, and FRZB in cerebrospinal fluid; and LMAN2L, NCAM1, and TIMP4 in plasma, delineating promising avenues to development of novel therapies.

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Section: Discussionmentioning

confidence: 99%

Uncovering novel drug targets for bipolar disorder: a Mendelian randomization analysis of brain, cerebrospinal fluid, and plasma proteomes

Jia,

Liu,

et al. 2024

Psychol. Med.

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“…This is in line with previous studies suggesting that the AP and Arc/ME represent easy access sites for circulating endogenous and exogenous eating-relevant hormones including amylin, glucagon-like peptide-1 and ghrelin ( 61 , 62 ). Interestingly, very recent evidence from the research team led by Dr D’Agostino ( 63 ), demonstrates that systemic administration of OEA (10 mg/kg) to food-deprived female mice produces a rapid and stable inhibition of Agouti-related protein positive neurons of the Arc, which are strongly activated during a negative energy balance to stimulate eating. In their ( 63 ) OEA’s inhibitory effect on these neurons was maximal at 5 min after i.p.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, very recent evidence from the research team led by Dr D’Agostino ( 63 ), demonstrates that systemic administration of OEA (10 mg/kg) to food-deprived female mice produces a rapid and stable inhibition of Agouti-related protein positive neurons of the Arc, which are strongly activated during a negative energy balance to stimulate eating. In their ( 63 ) OEA’s inhibitory effect on these neurons was maximal at 5 min after i.p. administration, thus mimicking the time course of OEA brain distribution observed in our experiment.…”

Section: Discussionmentioning

confidence: 99%

“To brain or not to brain”: evaluating the possible direct effects of the satiety factor oleoylethanolamide in the central nervous system

et al. 2023

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IntroductionOleoylethanolamide (OEA), an endogenous N-acylethanolamine acting as a gut-to-brain signal to control food intake and metabolism, has been attracting attention as a target for novel therapies against obesity and eating disorders. Numerous observations suggested that the OEA effects might be peripherally mediated, although they involve central pathways including noradrenergic, histaminergic and oxytocinergic systems of the brainstem and the hypothalamus. Whether these pathways are activated directly by OEA or whether they are downstream of afferent nerves is still highly debated. Some early studies suggested vagal afferent fibers as the main route, but our previous observations have contradicted this idea and led us to consider the blood circulation as an alternative way for OEA’s central actions.MethodsTo test this hypothesis, we first investigated the impact of subdiaphragmatic vagal deafferentation (SDA) on the OEA-induced activation of selected brain nuclei. Then, we analyzed the pattern of OEA distribution in plasma and brain at different time points after intraperitoneal administration in addition to measuring food intake.ResultsConfirming and extending our previous findings that subdiaphragmatic vagal afferents are not necessary for the eating-inhibitory effect of exogenous OEA, our present results demonstrate that vagal sensory fibers are also not necessary for the neurochemical effects of OEA. Rather, within a few minutes after intraperitoneal administration, we found an increased concentration of intact OEA in different brain areas, associated with the inhibition of food intake.ConclusionOur results support that systemic OEA rapidly reaches the brain via the circulation and inhibits eating by acting directly on selected brain nuclei.

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“…In addition to leptin, orexigenic neuropeptides are also negatively affected in the setting of hypothalamic inflammation with NPY/AgRP co-expressing neurons through gut-brain crosstalk with microglia being heavily involved [83]. Recent studies have suggested that hypothalamic AgRP neurons may also reciprocally promote TNF-α release through a top-down mechanism to worsen endotoxemia and energy balance [84]. Previous work suggests that bariatric surgery mitigates hypothalamic inflammation via gut-microglia crosstalk through a weight loss-independent manner [78] (Figure 3B).…”

Section: Bariatric Surgery Gut Microbiota Cytokines and Inflammationmentioning

confidence: 99%

Influence of Bariatric Surgery on Gut Microbiota Composition and Its Implication on Brain and Peripheral Targets

Hamamah,

Hajnal,

Covasa

2024

Nutrients

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Obesity remains a significant global health challenge, with bariatric surgery remaining as one of the most effective treatments for severe obesity and its related comorbidities. This review highlights the multifaceted impact of bariatric surgery beyond mere physical restriction or nutrient malabsorption, underscoring the importance of the gut microbiome and neurohormonal signals in mediating the profound effects on weight loss and behavior modification. The various bariatric surgery procedures, such as Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), act through distinct mechanisms to alter the gut microbiome, subsequently impacting metabolic health, energy balance, and food reward behaviors. Emerging evidence has shown that bariatric surgery induces profound changes in the composition of the gut microbiome, notably altering the Firmicutes/Bacteroidetes ratio and enhancing populations of beneficial bacteria such as Akkermansia. These microbiota shifts have far-reaching effects beyond gut health, influencing dopamine-mediated reward pathways in the brain and modulating the secretion and action of key gut hormones including ghrelin, leptin, GLP-1, PYY, and CCK. The resultant changes in dopamine signaling and hormone levels contribute to reduced hedonic eating, enhanced satiety, and improved metabolic outcomes. Further, post-bariatric surgical effects on satiation targets are in part mediated by metabolic byproducts of gut microbiota like short-chain fatty acids (SCFAs) and bile acids, which play a pivotal role in modulating metabolism and energy expenditure and reducing obesity-associated inflammation, as well as influencing food reward pathways, potentially contributing to the regulation of body weight and reduction in hedonic eating behaviors. Overall, a better understanding of these mechanisms opens the door to developing non-surgical interventions that replicate the beneficial effects of bariatric surgery on the gut microbiome, dopamine signaling, and gut hormone regulation, offering new avenues for obesity treatment.

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Hypothalamic AgRP neurons exert top-down control on systemic TNF-α release during endotoxemia

Cited by 4 publications

References 40 publications

Uncovering novel drug targets for bipolar disorder: a Mendelian randomization analysis of brain, cerebrospinal fluid, and plasma proteomes

Uncovering novel drug targets for bipolar disorder: a Mendelian randomization analysis of brain, cerebrospinal fluid, and plasma proteomes

“To brain or not to brain”: evaluating the possible direct effects of the satiety factor oleoylethanolamide in the central nervous system

Influence of Bariatric Surgery on Gut Microbiota Composition and Its Implication on Brain and Peripheral Targets

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