Mitochondrial uncoupler SHC517 reverses obesity in mice without affecting food intake

Single-minded 1 (SIM1) mutations are associated with obesity in mice and humans. Haploinsufficiency of mouse Sim1 causes hyperphagic obesity with increased linear growth and enhanced sensitivity to a high-fat diet, a phenotype similar to that of agouti yellow and melanocortin 4 receptor knockout mice. To investigate the effects of increased Sim1 dosage, we generated transgenic mice that overexpress human SIM1 and examined their phenotype. Compared with wild-type mice, SIM1 transgenic mice had no obvious phenotype on a low-fat chow diet but were resistant to diet-induced obesity on a high-fat diet due to reduced food intake with no change in energy expenditure. The SIM1 transgene also completely rescued the hyperphagia and partially rescued the obesity of agouti yellow mice, in which melanocortin signaling is abrogated. Our results indicate that the melanocortin 4 receptor signals through Sim1 or its transcriptional targets in controlling food intake but not energy expenditure.

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Moo1 obesity quantitative trait locus in BTBR T+ Itpr3tf/J mice increases food intake

Physiological Genomics ◽

10.1152/physiolgenomics.00159.2012 ◽

2013 ◽

Vol 45 (5) ◽

pp. F191-F199 ◽

Cited By ~ 2

Author(s):

Subashini Karunakaran ◽

Akiff Manji ◽

Chenhua Serena Yan ◽

Zi-Jun John Wu ◽

Susanne M. Clee

Keyword(s):

Quantitative Trait Locus ◽

Food Intake ◽

Quantitative Trait ◽

Factors Affecting ◽

New Therapeutic Approaches ◽

Diet Induced Obesity ◽

Clinical Consequences ◽

Prevalence Of Obesity ◽

Obesity In Mice ◽

Trait Locus

The rising prevalence of obesity is one of the greatest health challenges facing the world today. Discovery of genetic factors affecting obesity risk will provide important insight to its etiology that could suggest new therapeutic approaches. We have previously identified the Modifier of obese 1 ( Moo1) quantitative trait locus (QTL) in a cross between leptin-deficient BTBR T+ Itpr3tf/J (BTBR) and C57BL/6J (B6) mice. Understanding the mechanism by which this locus acts will aid in the identification of candidate genes. Here we refined the location of this QTL and sought to determine the mechanism by which Moo1 affects body weight. We found that the effects of Moo1 also alter high fat diet-induced obesity in mice having functional leptin. In detailed metabolic analyses we determined that this locus acts by increasing food intake in BTBR mice, without affecting energy expenditure. The expression levels of the main molecular mediators of food intake in the hypothalamus were not altered, suggesting this locus affects an independent pathway, consistent with its identification in mice lacking functional leptin. Finally, we show that the increased adiposity resulting from Moo1 is sufficient to affect glucose tolerance. These studies show that the Moo1 obesity QTL affects food intake, likely through a novel mechanism, and indicate that modulation of the underlying pathway may not only ameliorate obesity but also its clinical consequences.

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PARP1 deficiency exacerbates diet-induced obesity in mice

Journal of Endocrinology ◽

10.1677/joe-09-0402 ◽

2010 ◽

Vol 205 (3) ◽

pp. 243-252 ◽

Cited By ~ 37

Author(s):

Kishor Devalaraja-Narashimha ◽

Babu J Padanilam

Keyword(s):

Insulin Resistance ◽

Weight Gain ◽

Food Intake ◽

Heat Production ◽

Diet Induced Obesity ◽

Insulin Tolerance ◽

Protein Functions ◽

Normal Chow ◽

Obesity In Mice ◽

Fat Reabsorption

Poly (ADP-ribose) polymerase-1 (PARP1) regulates gene expression as a transcriptional cofactor and protein functions via poly (ADP-ribosyl)ation. This study was aimed to determine the effect of Parp1 gene deficiency on diet-induced obesity and energy metabolism. Parp1-knockout (Parp-KO) and wild-type (WT) mice on the same genetic background were fed either normal chow or high-fat (HF) diet. Food intake and weight gain were monitored weekly. Plasma levels of glucose, leptin, and insulin were monitored monthly. At 19 weeks, locomotor activity, body composition, respiratory quotient and heat production, glucose and insulin tolerance, and fat reabsorption were analyzed. Parp-KO mice are highly susceptible to diet-induced obesity, accumulation of fat tissue, and they develop hyperleptinemia and insulin resistance and glucose intolerance compared with their WT counterparts. The increased weight gain is due to decreased metabolic rate, heat production, and total energy expenditure (EE). Paradoxically, food intake is less, and the motor activity and oxidation of fat are higher in Parp-KO mice. Absorption of fatty acids is not altered between the groups after HF diet. These results suggest that malfunction of PARP1 signaling exacerbates diet-induced obesity, hyperleptinemia, and insulin resistance, and that it decreases EE in 129 mice.

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Gastric Expression of Plasminogen Activator Inhibitor (PAI)-1 Is Associated with Hyperphagia and Obesity in Mice

Endocrinology ◽

10.1210/en.2012-1913 ◽

2013 ◽

Vol 154 (2) ◽

pp. 718-726 ◽

Cited By ~ 10

Author(s):

Susan Kenny ◽

Joanne Gamble ◽

Suzanne Lyons ◽

Nikolina Vlatković ◽

Rod Dimaline ◽

...

Keyword(s):

Food Intake ◽

Plasminogen Activator ◽

Nucleus Tractus Solitarius ◽

Plasma Concentrations ◽

Plasminogen Activator Inhibitor ◽

Wild Type ◽

Urokinase Plasminogen Activator Receptor ◽

Obesity In Mice ◽

Activator Inhibitor ◽

Pai 1

The adipokine plasminogen activator inhibitor (PAI)-1 is increased in plasma of obese individuals and exhibits increased expression in the stomachs of individuals infected with Helicobacter. To investigate the relevance of gastric PAI-1, we used 1.1 kb of the H+/K+β subunit promoter to overexpress PAI-1 specifically in mouse gastric parietal cells (PAI-1-H/Kβ mice). We studied the physiological, biochemical, and behavioral characteristics of these and mice null for PAI-1 or a putative receptor, urokinase plasminogen activator receptor (uPAR). PAI-1-H/Kβ mice had increased plasma concentrations of PAI-1 and increased body mass, adiposity, and hyperphagia compared with wild-type mice. In the latter, food intake was inhibited by cholecystokinin (CCK)8s, but PAI-1-H/Kβ mice were insensitive to the satiating effects of CCK8s. PAI-1-H/Kβ mice also had significantly reduced expression of c-fos in the nucleus tractus solitarius in response to CCK8s and refeeding compared with wild-type mice. Exogenous PAI-1 reversed the effects of CCK8s on food intake and c-fos levels in the nucleus tractus solitarius of wild-type mice, but not uPAR-null mice. Infection of C57BL/6 mice with Helicobacter felis increased gastric abundance of PAI-1 and reduced the satiating effects of CCK8s, whereas the response to CCK8s was maintained in infected PAI-1–null mice. In cultured vagal afferent neurons, PAI-1 inhibited stimulation of neuropeptide Y type 2 receptor (Y2R) expression by CCK8s. Thus, gastric expression of PAI-1 is associated with hyperphagia, moderate obesity, and resistance to the satiating effects of CCK indicating a new role in suppressing signals from the upper gut that inhibit food intake.

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Oxytocin signaling in the posterior hypothalamus prevents hyperphagic obesity in mice

10.1101/2021.11.29.470473 ◽

2021 ◽

Author(s):

Kengo Inada ◽

Kazuko Tsujimoto ◽

Masahide Yoshida ◽

Katsuhiko Nishimori ◽

Kazunari Miyamichi

Keyword(s):

Body Weight ◽

Food Intake ◽

Neural Circuit ◽

Intraperitoneal Administration ◽

Whole Body ◽

Hypothalamic Nucleus ◽

Physiological Regulation ◽

Hypothalamic Regulation ◽

Obesity In Mice ◽

Anorexigenic Effect

Decades of studies have revealed molecular and neural circuit bases for body weight homeostasis. Neural hormone oxytocin (OT) has received attention in this context because it is produced by neurons in the paraventricular hypothalamic nucleus (PVH), a known output center of hypothalamic regulation of appetite. OT has an anorexigenic effect, as shown in human studies, and can mediate satiety signals in rodents. However, the function of OT signaling in the physiological regulation of appetite has remained in question, because whole-body knockout (KO) of OT or OT receptor (OTR) has little effect on food intake. We herein show that acute conditional KO (cKO) of OT selectively in the adult PVH, but not in the supraoptic nucleus, markedly increases body weight and food intake, with an elevated level of plasma triglyceride and leptin. Intraperitoneal administration of OT rescues the hyperphagic phenotype of the PVH OT cKO model. Furthermore, we show that cKO of OTR selectively in the posterior hypothalamic regions, which include the primary centers for appetite regulations, phenocopies hyperphagic obesity. Collectively, these data functionally reveal that OT signaling in the posterior hypothalamic regions suppresses excessive food intake.

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Deletion of the Cold Thermoreceptor TRPM8 Increases Heat Loss and Food Intake Leading to Reduced Body Temperature and Obesity in Mice

Journal of Neuroscience ◽

10.1523/jneurosci.3002-17.2018 ◽

2018 ◽

Vol 38 (15) ◽

pp. 3643-3656 ◽

Cited By ~ 18

Author(s):

Alfonso Reimúndez ◽

Carlos Fernández-Peña ◽

Guillermo García ◽

Rubén Fernández ◽

Purificación Ordás ◽

...

Keyword(s):

Food Intake ◽

Body Temperature ◽

Heat Loss ◽

Reduced Body ◽

Obesity In Mice

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Antiobesity Effect of a Melanin-Concentrating Hormone 1 Receptor Antagonist in Diet-Induced Obese Mice

Endocrinology ◽

10.1210/en.2004-1150 ◽

2005 ◽

Vol 146 (7) ◽

pp. 3080-3086 ◽

Cited By ~ 57

Author(s):

Satoshi Mashiko ◽

Akane Ishihara ◽

Akira Gomori ◽

Ryuichi Moriya ◽

Makoto Ito ◽

...

Keyword(s):

Food Intake ◽

Body Weight Gain ◽

Physiological Role ◽

Obese Mice ◽

Sprague Dawley ◽

Diet Induced Obesity ◽

Intracerebroventricular Infusion ◽

Orexigenic Peptide ◽

Melanin Concentrating Hormone ◽

Obesity In Mice

Abstract Melanin-concentrating hormone (MCH) is a cyclic orexigenic peptide expressed in the lateral hypothalamus, which plays an important role in regulating energy balance. To elucidate the physiological role of MCH in obesity development, the present study examined the effect of a selective MCH1 receptor (MCH1R) antagonist in the diet-induced obesity mouse model. The MCH1R antagonist has high affinity and selectivity for MCH-1R and potently inhibits intracerebroventricularly injected MCH-induced food intake in Sprague Dawley rats. Chronic intracerebroventricular infusion of the MCH1R antagonist (7.5 μg/d) completely suppressed body weight gain in diet-induced obese mice during the treatment periods and significantly decreased cumulative food intake, by 14%. Carcass analysis showed that the MCH1R antagonist resulted in a selective decrease of body fat in the diet-induced obese mice. In addition, the MCH1R antagonist ameliorated the obesity-related hypercholesterolemia, hyperinsulinemia, hyperglycemia, and hyperleptinemia. These results indicate that MCH has a major role in the development of diet-induced obesity in mice and that a MCH1R antagonist might be a useful candidate as an antiobesity agent.

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Timing of food intake is more potent than habitual voluntary exercise to prevent diet-induced obesity in mice

Chronobiology International ◽

10.1080/07420528.2018.1516672 ◽

2018 ◽

Vol 36 (1) ◽

pp. 57-74 ◽

Cited By ~ 7

Author(s):

Hiroki Okauchi ◽

Chiaki Hashimoto ◽

Reiko Nakao ◽

Katsutaka Oishi

Keyword(s):

Food Intake ◽

Voluntary Exercise ◽

Diet Induced Obesity ◽

Obesity In Mice

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Obesity and adiposity: the culprit of dietary protein efficacy

Clinical Science ◽

10.1042/cs20190583 ◽

2020 ◽

Vol 134 (4) ◽

pp. 389-401

Author(s):

Carla El-Mallah ◽

Omar Obeid

Keyword(s):

Food Intake ◽

Behavioural Change ◽

Physiological Mechanism ◽

Short Term ◽

The Past ◽

Body Adiposity ◽

Reduce Sugar ◽

Eye Opening ◽

Potential Strategy ◽

Limitations And Exceptions

Abstract Obesity and increased body adiposity have been alarmingly increasing over the past decades and have been linked to a rise in food intake. Many dietary restrictive approaches aiming at reducing weight have resulted in contradictory results. Additionally, some policies to reduce sugar or fat intake were not able to decrease the surge of obesity. This suggests that food intake is controlled by a physiological mechanism and that any behavioural change only leads to a short-term success. Several hypotheses have been postulated, and many of them have been rejected due to some limitations and exceptions. The present review aims at presenting a new theory behind the regulation of energy intake, therefore providing an eye-opening field for energy balance and a potential strategy for obesity management.

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