Three of a Kind: Control of the Expression of Liver-Expressed Antimicrobial Peptide 2 (LEAP2) by the Endocannabinoidome and the Gut Microbiome

Shen, Mélissa; Manca, Claudia; Suriano, Francesco; Nallabelli, Nayudu; Pechereau, Florent; Allam-Ndoul, Bénédicte; Iannotti, Fabio Arturo; Flamand, Nicolas; Veilleux, Alain; Cani, Patrice D.; Silvestri, Cristoforo; Marzo, Vincenzo Di

doi:10.3390/molecules27010001

Cited by 13 publications

(6 citation statements)

References 43 publications

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“…Beyond feeding, the finding that central LEAP2 can attenuate dopaminergic reward signaling warrants further studies of its effect in different dopamine-related psychiatric disorders, most distinctively addiction disorders where GHSR signaling already have been shown to be affected [17][18][19]48 . Interestingly, LEAP2 appears greatly affected by diet, as shown here and in previous studies 49,50 , as well as by the gut microbiome 51 . Importantly, we show here that even LEAP2 expression in deep brain structures are highly affected by diet.…”

Section: Discussionsupporting

confidence: 86%

“…As such, the current study was limited to only using male mice. Considering that there appears to be some sex-dependent differences in LEAP2 51, 52 , any such differences must be addressed to fully understand the effects of LEAP2. Further, we aimed to investigate the effects of acute central effects of LEAP2, and not the effects of systemic or prolonged elevated LEAP2, which further studies should address.…”

Section: Discussionmentioning

confidence: 99%

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Decoding the Influence of Central LEAP2 on Hedonic Food Intake and its association with Dopaminergic Reward Pathways

Tufvesson-Alm,

Zhang,

Aranäs

et al. 2023

Preprint

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The gut-brain peptide ghrelin and its receptor (GHSR) are established as a regulator of hunger and reward-processing. However, the recently recognized GHSR inverse agonist, liver-expressed antimicrobial peptide 2 (LEAP2), is less characterized. Given the role of GHSR in many central processes, and in particular reward, understanding the central effects of LEAP2 is of high interest to understand reward-related behaviors and disorders, including hedonic feeding in eating disorders. The present study aimed to elucidate LEAP2s central effect on reward-related behaviors through hedonic feeding and its mechanism. LEAP2 was administrated centrally in male mice and effectively reduced hedonic feeding but had no or little effect on homeostatic chow intake when a more palatable option was available. Strikingly, the effect on hedonic feeding was correlated to the preference of the palatable food option, where peanut butter showed the highest preference and the greatest reduction by LEAP2. Further, LEAP2 reduced the rewarding memory of high-preference foods, as well as attenuated the accumbal dopamine release associated with peanut butter exposure and eating. Interestingly, LEAP2 was widely expressed in the brain, and in particular in reward-related brain areas such as the laterodorsal tegmental area (LDTg). The expression in this area was also markedly altered when given free access to peanut butter. Accordingly, infusion of LEAP2 into the LDTg was sufficient to attenuate acute peanut butter eating. Taken together, the present results show that central LEAP2 has a profound effect on central dopaminergic reward signaling and affects several aspects of hedonic eating. The present study highlights LEAP2s effect on reward, which may have application not only for hedonic feeding, but for other reward-related psychiatric disorders as well.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Decoding the Influence of Central LEAP2 on Hedonic Food Intake and its association with Dopaminergic Reward Pathways

Tufvesson-Alm,

Zhang,

Aranäs

et al. 2023

Preprint

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“…Through the hepatic-gastric-brain axis (98), Leap2 may impact eating and energy balance. Latest research demonstrated that Leap2 also mediates the outcomes of food consumption and energy metabolism through the endogenous cannabinoid system (eCBome)-gut microbiome (mBIome) axis (106). In summary, LEAP2 can improve diabetes by inhibiting brain intake-related energy metabolism.…”

Section: Effect Of Leap2 On Energy Metabolismmentioning

confidence: 99%

Feeding-induced hepatokines and crosstalk with multi-organ: A novel therapeutic target for Type 2 diabetes

Chen

Wang²,

Wang³

et al. 2023

Front. Endocrinol.

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Hyperglycemia, which can be caused by either an insulin deficit and/or insulin resistance, is the main symptom of Type 2 diabetes, a significant endocrine metabolic illness. Conventional medications, including insulin and oral antidiabetic medicines, can alleviate the signs of diabetes but cannot restore insulin release in a physiologically normal amount. The liver detects and reacts to shifts in the nutritional condition that occur under a wide variety of metabolic situations, making it an essential organ for maintaining energy homeostasis. It also performs a crucial function in glucolipid metabolism through the secretion of hepatokines. Emerging research shows that feeding induces hepatokines release, which regulates glucose and lipid metabolism. Notably, these feeding-induced hepatokines act on multiple organs to regulate glucolipotoxicity and thus influence the development of T2DM. In this review, we focus on describing how feeding-induced cross-talk between hepatokines, including Adropin, Manf, Leap2 and Pcsk9, and metabolic organs (e.g.brain, heart, pancreas, and adipose tissue) affects metabolic disorders, thus revealing a novel approach for both controlling and managing of Type 2 diabetes as a promising medication.

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“…The major alterations of eCBs and eCB-like lipid mediators in the brain widely reported in germ free (GF) mice (Manca et al, 2020b), further corroborate the idea that the eCB signaling system mediates many functions of the bidirectional microbiota-gut-brain communication. Even beyond the implications for NDDs, there is now evidence that the complex homeostatic role exerted by the eCB system and eCBlike mediators is including unpredicted functions such as those recently described for the intestinal expression of the liverexpressed antimicrobial peptide 2 (LEAP2), which is partially regulated by eCB system-microbiota interaction and is important for the impact of nutrients on energy metabolism (Shen et al, 2022).…”

Section: Ecbs-microbiota Reciprocal Contamination: Implications For A...mentioning

confidence: 99%

The Endocannabinoids-Microbiota Partnership in Gut-Brain Axis Homeostasis: Implications for Autism Spectrum Disorders

2022

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The latest years have witnessed a growing interest towards the relationship between neuropsychiatric disease in children with autism spectrum disorders (ASD) and severe alterations in gut microbiota composition. In parallel, an increasing literature has focused the attention towards the association between derangement of the endocannabinoids machinery and some mechanisms and symptoms identified in ASD pathophysiology, such as alteration of neural development, immune system dysfunction, defective social interaction and stereotypic behavior. In this narrative review, we put together the vast ground of endocannabinoids and their partnership with gut microbiota, pursuing the hypothesis that the crosstalk between these two complex homeostatic systems (bioactive lipid mediators, receptors, biosynthetic and hydrolytic enzymes and the entire bacterial gut ecosystem, signaling molecules, metabolites and short chain fatty acids) may disclose new ideas and functional connections for the development of synergic treatments combining “gut-therapy,” nutritional intervention and pharmacological approaches. The two separate domains of the literature have been examined looking for all the plausible (and so far known) overlapping points, describing the mutual changes induced by acting either on the endocannabinoid system or on gut bacteria population and their relevance for the understanding of ASD pathophysiology. Both human pathology and symptoms relief in ASD subjects, as well as multiple ASD-like animal models, have been taken into consideration in order to provide evidence of the relevance of the endocannabinoids-microbiota crosstalk in this major neurodevelopmental disorder.

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Three of a Kind: Control of the Expression of Liver-Expressed Antimicrobial Peptide 2 (LEAP2) by the Endocannabinoidome and the Gut Microbiome

Cited by 13 publications

References 43 publications

Decoding the Influence of Central LEAP2 on Hedonic Food Intake and its association with Dopaminergic Reward Pathways

Decoding the Influence of Central LEAP2 on Hedonic Food Intake and its association with Dopaminergic Reward Pathways

Feeding-induced hepatokines and crosstalk with multi-organ: A novel therapeutic target for Type 2 diabetes

The Endocannabinoids-Microbiota Partnership in Gut-Brain Axis Homeostasis: Implications for Autism Spectrum Disorders

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