A novel and selective melanin-concentrating hormone receptor 1 antagonist ameliorates obesity and hepatic steatosis in diet-induced obese rodent models

Kawata, Y.; Okuda, Suguru; Hotta, Natsu; Igawa, Hideyuki; Takahashi, Masashi; Ikoma, Minoru; Kasai, Shizuo; Ando, Ayumi; Satomi, Yoshinori; Nishida, Mayumi; Nakayama, Masaharu; Yamamoto, Satoshi; Nagisa, Yasutaka; Takekawa, Shiro

doi:10.1016/j.ejphar.2016.12.018

Cited by 22 publications

(20 citation statements)

References 51 publications

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“…Chronic infusion of MCH causes obesity [182], and MCH deletion causes resistance to diet-induced obesity in mice [183,184]. Recently, a selective MCH receptor 1 antagonist is reported successfully ameliorating obesity and hepatic steatosis in mouse NAFLD models [185].…”

Section: Brain and Nafldmentioning

confidence: 99%

Multiple organs involved in the pathogenesis of non-alcoholic fatty liver disease

Wang

2020

Cell Biosci

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Non-alcoholic fatty liver disease (NAFLD) represents the leading cause of chronic liver disease worldwide and the anticipated health burden is huge. There are limited therapeutic approaches for NAFLD now. It’s imperative to get a better understanding of the disease pathogenesis if new treatments are to be discovered. As the hepatic manifestation of metabolic syndrome, this disease involves complex interactions between different organs and regulatory pathways. It’s increasingly clear that brain, gut and adipose tissue all contribute to NAFLD pathogenesis and development, in view of their roles in energy homeostasis. In the present review, we try to summarize currently available data regarding NAFLD pathogenesis and to lay a particular emphasis on the inter-organ crosstalk evidence.

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Section: Brain and Nafldmentioning

confidence: 99%

Multiple organs involved in the pathogenesis of non-alcoholic fatty liver disease

Wang

2020

Cell Biosci

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“…Accordingly, stimulation of each of these two isoforms is expected to have differential effects on neurologic function and downstream effects (that may possibly be in the opposite direction) [ 41 , 42 ]. MCH thus appears to be an important mediator of metabolic processes, food intake, energy expenditure, obesity, mood control, stress and sleep-wake cycles.…”

Section: Introductionmentioning

confidence: 99%

Insulin-Sensitizer Effects of Fenugreek Seeds in Parallel with Changes in Plasma MCH Levels in Healthy Volunteers

Kiss

Szabó

Gesztelyi

et al. 2018

IJMS

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In developed, developing and low-income countries alike, type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases, the severity of which is substantially a consequence of multiple organ complications that occur due to long-term progression of the disease before diagnosis and treatment. Despite enormous investment into the characterization of the disease, its long-term management remains problematic, with those afflicted enduring significant degradation in quality-of-life. Current research efforts into the etiology and pathogenesis of T2DM, are focused on defining aberrations in cellular physiology that result in development of insulin resistance and strategies for increasing insulin sensitivity, along with downstream effects on T2DM pathogenesis. Ongoing use of plant-derived naturally occurring materials to delay the onset of the disease or alleviate symptoms is viewed by clinicians as particularly desirable due to well-established efficacy and minimal toxicity of such preparations, along with generally lower per-patient costs, in comparison to many modern pharmaceuticals. A particularly attractive candidate in this respect, is fenugreek, a plant that has been used as a flavouring in human diet through recorded history. The present study assessed the insulin-sensitizing effect of fenugreek seeds in a cohort of human volunteers, and tested a hypothesis that melanin-concentrating hormone (MCH) acts as a critical determinant of this effect. A test of the hypothesis was undertaken using a hyperinsulinemic euglycemic glucose clamp approach to assess insulin sensitivity in response to oral administration of a fenugreek seed preparation to healthy subjects. Outcomes of these evaluations demonstrated significant improvement in glucose tolerance, especially in patients with impaired glucose responses. Outcome data further suggested that fenugreek seed intake-mediated improvement in insulin sensitivity correlated with reduction in MCH levels.

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“…Since MCH is an essential mediator of appetite regulation ( Nahon, 2006 ), we hypothesized a potent effect of TDCA/valine on MCH suppression. Consistently, the combinatorial administration of a selective MCHR1 antagonist ( Kawata et al, 2017 ) and TDCA/valine failed to elicit additional weight loss, suggesting that TDCA/valine acts at least in part through inhibiting MCH. This hypothesis was confirmed in DIO Wistar rats showing a diminished responsiveness to TDCA/valine treatment when treated intrathecally with recombinant MCH.…”

Section: Discussionmentioning

confidence: 79%

Restored TDCA and valine levels imitate the effects of bariatric surgery

Quante

Iske

Heinbokel

et al. 2021

eLife

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Background: Obesity is widespread and linked to various co-morbidities. Bariatric surgery has been identified as the only effective treatment, promoting sustained weight loss and the remission of co-morbidities. Methods: Metabolic profiling was performed on diet induced obese (DIO) mice, lean mice and DIO mice that underwent sleeve gastrectomies. In addition, mice were subjected to i.p. injections with TDCA and valine. Indirect calorimetry was performed to assess food intake and energy expenditure. Expression of appetite regulating hormones was assessed through quantification of isolated RNA from dissected hypothalamus tissue. Subsequently, i.p. injections with an MCH antagonist and intrathecal administration of melanin-concentrating hormone were performed and weight loss was monitored. Results: Mass-spectrometric metabolomic profiling revealed significantly reduced systemic levels of TDCA and L-valine in DIO mice. TDCA and L-Valine levels were restored after sleeve gastrectomies (SGx) in both human and mice to levels comparable with lean controls. Systemic treatment with TDCA and valine induced a profound weight loss analogous to effects observed after SGx. Utilizing indirect calorimetry, we confirmed reduced food intake as causal for TDCA/valine-mediated weight loss via a central inhibition of the melanin-concentrating hormone. Conclusions: In summary, we identified restored TDCA/valine levels as an underlying mechanism of SGx-derived effects on weight loss. Of translational relevance, TDCA and L-valine are presented as novel agents promoting weight loss while reversing obesity-associated metabolic disorders.

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A novel and selective melanin-concentrating hormone receptor 1 antagonist ameliorates obesity and hepatic steatosis in diet-induced obese rodent models

Cited by 22 publications

References 51 publications

Multiple organs involved in the pathogenesis of non-alcoholic fatty liver disease

Multiple organs involved in the pathogenesis of non-alcoholic fatty liver disease

Insulin-Sensitizer Effects of Fenugreek Seeds in Parallel with Changes in Plasma MCH Levels in Healthy Volunteers

Restored TDCA and valine levels imitate the effects of bariatric surgery

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