Melanin-Concentrating Hormone acts through hypothalamic kappa opioid system and p70S6K to stimulate acute food intake

Abstract

Melanin-Concentrating Hormone (MCH) is one of the most relevant orexigenic factors specifically located in the lateral hypothalamic area (LHA), with its physiological relevance demonstrated in studies using several genetically manipulated mice models. However, the central mechanisms controlling MCH-induced hyperphagia remain largely uncharacterized. Here, we show that central injection of MCH in mice deficient for kappa opoid receptor (k-OR) failed to stimulate feeding. To determine the hypothalamic area responsible for this MCH/k-OR interaction, we performed virogenetic studies and found that downregulation of k-OR by adeno-associated viruses (shOprk1-AAV) in LHA, but not in other hypothalamic nuclei, was sufficient to block MCH-induced food intake. Next, we sought to investigate the molecular signaling pathway within the LHA that mediates acute central MCH stimulation of food intake. We found that MCH activates k-OR and that increased levels of phosphorylated extracellular signal regulated kinase (ERK) are associated with downregulation of phospho-S6 Ribosomal Protein. This effect was prevented when a pharmacological inhibitor of k-OR was co-administered with MCH. Finally, the specific activation of the direct upstream regulator of S6 (p70S6K) in the LHA attenuated MCH-stimulated food consumption. Our results reveal that lateral hypothalamic k-OR system modulates the orexigenic action of MCH via the p70S6K/S6 pathway.

Central nicotine induces browning through hypothalamic κ opioid receptor

“…The hypothalamic nuclei were targeted bilaterally using a 25-gauge needle (Hamilton; Reno, NV, USA). The injections were directed to the following stereotaxic coordinates: (a) for the VMH: 2.4/3.2 mm posterior to the bregma (two injections were performed in each VMH), ±0.6 mm lateral to midline and 10.1 mm ventral 3,33,38,47–49 and (b) for the LHA: 2.85 mm posterior to the bregma, ±2 mm lateral to the midline and 8.1 mm ventral 24,33 . Adeno-associated viral (AAV) vectors (1 × 10 9 genomic copies µl −1 ) encoding or not rat KOR short-hairpin RNAs 23 were delivered at a rate of 200 nl min −1 for 5 min (1 µl at each injection site) to specifically silence the expression of Opkr1 mRNA in the VMH or the LHA.…”

“…At the central level, the opioid system can act in multiple brain areas. For example, it is known that dynorphin (DYN, an endogenous ligand of KOR) modulates food intake and fat mass by increasing SNS activity 22 and that hypothalamic KOR signaling mediates the orexigenic action of ghrelin 23 and melanin-concentrating hormone (MCH) 24 . In addition, mice lacking MOR, KOR, or DOR resist the development of diet-induced obesity, despite hyperphagia, due to the increased energy expenditure, leading to an overall improvement of the metabolic phenotype 25–27 .…”

Impact of liver-specific GLUT8 silencing on fructose-induced inflammation and omega oxidation

“…After incubation, an Alexa594-conjugated secondary antibody or an Alexa488-conjugated secondary antibody was added (1h, room temperature). Coverslips were mounted with Fluoro-Gel (Electron Microscopy Sciences -17985-10) and DAPI (Cell signalling #4083) (Romero-Pico et al, 2018;Romero-Pico et al, 2013).…”

Melanin-concentrating hormone in rat nucleus accumbens or lateral hypothalamus differentially impacts morphine and food seeking behaviors

“…One critical issue is whether MCH’s inhibitory effect on NAc DA only targets addiction-like behaviors without affecting other natural reward-motivated behaviors. This issue is particularly important, as LH MCH is known to play an important role in food intake, via activation of the feeding neurocircuits within the arcuate and paraventricular nuclei of the hypothalamus (Abbott et al, 2003; Romero-Pico et al, 2018; Shimada et al, 1998; Qu et al, 1996). Hypothalamic MCH can also travel to several extrahypothalamic regions to modulate feeding.…”