Involvement of POMC neurons in LEAP2 regulation of food intake and body weight

Abstract

Liver-expressed antimicrobial peptide 2 (LEAP2) is a newly discovered antagonist of the growth hormone secretagogue receptor (GHSR) and is considered the first endogenous peptide that can antagonize the metabolic actions of ghrelin. The effects of ghrelin administration on feeding behavior, body weight, and energy metabolism involve the activation of orexigenic neurons in the arcuate nucleus (ARC) of the hypothalamus. It is unclear, however, if LEAP2 applied directly to the ARC of the hypothalamus affects these metabolic processes. Here, we show that overexpression of LEAP2 in the ARC through adeno-associated virus (AAV) reduced food intake and body weight in wild-type (WT) mice fed chow and a high-fat diet (HFD) and improved metabolic disorders. LEAP2 overexpression in the ARC overrides both central and peripheral ghrelin action on a chow diet. Interestingly, this AAV-LEAP2 treatment increased proopiomelanocortin (POMC) expression while agouti-related peptide (AGRP)/neuropeptide Y (NPY) and GHSR levels remained unchanged in the hypothalamus. Additionally, intracerebroventricular (i.c.v.) administration of LEAP2 decreased food intake, increased POMC neuronal activity, and repeated LEAP2 administration to mice induced body weight loss. Using chemogenetic manipulations, we found that inhibition of POMC neurons abolished the anorexigenic effect of LEAP2. These results demonstrate that central delivery of LEAP2 leads to appetite-suppressing and body weight reduction, which might require activation of POMC neurons in the ARC.

Plasma LEAP-2 Following a Low-Calorie Diet with or without Interval Exercise in Women with Obesity

“…In fact, in mice fed ad libitum, intracerebroventricular co-administration of LEAP-2 and neuropeptide Y reduced food intake compared with intracerebroventricular neuropeptide Y administration only [ 20 ]. In contrast, LEAP-2 overexpression has been reported to increase pro-opiomelanocortin (POMC) mRNA/protein and intracerebroventricular LEAP-2 administration increased c-fos activity in POMC neurons, thereby highlighting potential anorexigenic effects on neurons to reduce body weight [ 29 ]. This is consistent with work demonstrating through use of a fluorescent-labelled n -terminal LEAP-2 fragment, that LEAP-2 binds to growth hormone secretagogue receptor-1a expressing brain regions (e.g., hypothalamic nuclei, hippocampal dentate gyrus, and medulla) to inhibit food intake [ 30 ].…”

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

“…Interestingly, in animals with free access to peanut butter, a strong reduction of LEAP2 mRNA expression could be observed (two-way ANOVA, effect of diet: F (1, 82) =59.62, p<0.0001, interaction effect: F (8, 82) =2.59, p=0.014), and in particular areas associated with reward, such as NAc (p=0.022), VTA (p=0.00068) and LDTg (p<0.0001), and memory, e.g., hippocampus (p=0.0046). Notably, hypothalamus, which is strongly associated with homeostatic eating and energy homeostasis 3, 33, 34 , had the lowest baseline expression, and was not affected by hedonic feeding (p=0.75)…”

“…Surprisingly, in this study, hypothalamic LEAP2 appeared to be the least important for hedonic feeding, considering its low LEAP2 expression and that free hedonic feeding did not alter that expression. A previous study has shown that overexpression of LEAP2 in hypothalamus reduces both chow and high-fat diet consumption 34 , an effect thought to be mediated through arcuate nucleus proopiomelanocortin neurons. Therefore, it appears likely that, although not found here, hypothalamic LEAP2 would affect food intake.…”

The role of TRPV ion channels in adipocyte differentiation: What is the evidence?

“…Previous study reported that capsaicin activates TRPV1, which increases glucagon like peptide‐1 (GLP‐1) protein levels and consequently reduces ghrelin (a hunger and energy state‐related hormone) levels in the gut 111 . Arch nucleus contains proopiomelanocortin (ARC POMC) neurons are key regulators of energy homeostasis 134,135 . Many studies have proved that stimulating POMC neurons reduces food intake and restraints obesity 136,137 .…”

“…111 Arch nucleus contains proopiomelanocortin (ARC POMC) neurons are key regulators of energy homeostasis. 134,135 Many studies have proved that stimulating POMC neurons reduces food intake and restraints obesity. 136,137 It showed activation of TRPV1-like receptor induces the release of anorexigenic α-melanocyte-stimulating hormone from ARC POMC neurons and consequently reduces food intake.…”