A novel chemical uncoupler ameliorates obesity and related phenotypes in mice with diet-induced obesity by modulating energy expenditure and food intake

Diabetologia ◽  
2013 ◽  
Vol 56 (10) ◽  
pp. 2297-2307 ◽  
Author(s):  
Y.-Y. Fu ◽  
M. Zhang ◽  
N. Turner ◽  
L.-N. Zhang ◽  
T.-C. Dong ◽  
...  
Keyword(s):  
Food Intake ◽  
Energy Expenditure ◽  
Diet Induced Obesity ◽  
Chemical Uncoupler

scholarly journals Susceptibility to diet induced obesity at thermoneutral conditions is independent of UCP1

2021 ◽  
Author(s):  
Sebastian Dieckmann ◽  
Akim Strohmeyer ◽  
Monja Willershaeuser ◽  
Stefanie Maurer ◽  
Wolfgang Wurst ◽  
...  
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Energy Expenditure ◽  
Knockout Mice ◽  
Body Weight Gain ◽  
Uncoupling Protein ◽  
Exon 2 ◽  
Diet Induced Obesity ◽  
Brown Adipose ◽  
Knockout Model

Objective Activation of uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) upon cold stimulation leads to substantial increase in energy expenditure to defend body temperature. Increases in energy expenditure after a high caloric food intake, termed diet-induced thermogenesis, are also attributed to BAT. These properties render BAT a potential target to combat diet-induced obesity. However, studies investigating the role of UCP1 to protect against diet-induced obesity are controversial and rely on the phenotyping of a single constitutive UCP1-knockout model. To address this issue, we generated a novel UCP1-knockout model by Cre-mediated deletion of Exon 2 in the UCP1 gene. We studied the effect of constitutive UCP1 knockout on metabolism and the development of diet-induced obesity. Methods UCP1 knockout and wildtype mice were housed at 30°C and fed a control diet for 4-weeks followed by 8-weeks of high-fat diet. Body weight and food intake were monitored continuously over the course of the study and indirect calorimetry was used to determine energy expenditure during both feeding periods. Results Based on Western blot analysis, thermal imaging and noradrenaline test, we confirmed the lack of functional UCP1 in knockout mice. However, body weight gain, food intake and energy expenditure were not affected by deletion of UCP1 gene function during both feeding periods. Conclusion Conclusively, we show that UCP1 does not protect against diet-induced obesity at thermoneutrality. Further we introduce a novel UCP1-KO mouse enabling the generation of conditional UCP1-knockout mice to scrutinize the contribution of UCP1 to energy metabolism in different cell types or life stages.

scholarly journals Antiobesity Effects of the β-Cell Hormone Amylin in Diet-Induced Obese Rats: Effects on Food Intake, Body Weight, Composition, Energy Expenditure, and Gene Expression

Endocrinology ◽  
2006 ◽  
Vol 147 (12) ◽  
pp. 5855-5864 ◽  
Author(s):  
Jonathan D. Roth ◽  
Heather Hughes ◽  
Eric Kendall ◽  
Alain D. Baron ◽  
Christen M. Anderson
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Energy Expenditure ◽  
Respiratory Quotient ◽  
Metabolic Effects ◽  
Mrna Levels ◽  
Lean Tissue ◽  
Reduced Body ◽  
Diet Induced Obesity ◽  
Cell Hormone

Effects of amylin and pair feeding (PF) on body weight and metabolic parameters were characterized in diet-induced obesity-prone rats. Peripherally administered rat amylin (300 μg/kg·d, 22d) reduced food intake and slowed weight gain: approximately 10% (P < 0.05), similar to PF. Fat loss was 3-fold greater in amylin-treated rats vs. PF (P < 0.05). Whereas PF decreased lean tissue (P < 0.05 vs. vehicle controls; VEH), amylin did not. During wk 1, amylin and PF reduced 24-h respiratory quotient (mean ± se, 0.82 ± 0.0, 0.81 ± 0.0, respectively; P < 0.05) similar to VEH (0.84 ± 0.01). Energy expenditure (EE mean ± se) tended to be reduced by PF (5.67 ± 0.1 kcal/h·kg) and maintained by amylin (5.86 ± 0.1 kcal/h·kg) relative to VEH (5.77 ± 0.0 kcal/h·kg). By wk 3, respiratory quotient no longer differed; however, EE increased with amylin treatment (5.74 ± 0.09 kcal/·kg; P < 0.05) relative to VEH (5.49 ± 0.06) and PF (5.38 ± 0.07 kcal/h·kg). Differences in EE, attributed to differences in lean mass, argued against specific amylin-induced thermogenesis. Weight loss in amylin and pair-fed rats was accompanied by similar increases arcuate neuropeptide Y mRNA (P < 0.05). Amylin treatment, but not PF, increased proopiomelanocortin mRNA levels (P < 0.05 vs. VEH). In a rodent model of obesity, amylin reduced body weight and body fat, with relative preservation of lean tissue, through anorexigenic and specific metabolic effects.

scholarly journals SIM1 Overexpression Partially Rescues Agouti Yellow and Diet-Induced Obesity by Normalizing Food Intake

Endocrinology ◽  
2006 ◽  
Vol 147 (10) ◽  
pp. 4542-4549 ◽  
Author(s):  
Bassil M. Kublaoui ◽  
J. Lloyd Holder ◽  
Kristen P. Tolson ◽  
Terry Gemelli ◽  
Andrew R. Zinn
Keyword(s):  
Food Intake ◽  
Energy Expenditure ◽  
Transgenic Mice ◽  
High Fat Diet ◽  
Chow Diet ◽  
High Fat ◽  
Enhanced Sensitivity ◽  
Diet Induced Obesity ◽  
Melanocortin 4 Receptor ◽  
Obesity In Mice

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.

scholarly journals STAT3 but Not ERK2 Is a Crucial Mediator Against Diet-Induced Obesity via VMH Neurons

2021 ◽  
Author(s):  
Gabriel Henrique Marques Gonçalves ◽  
Sabrina Mara Tristão ◽  
Rafaella Eduarda Volpi ◽  
Gislaine Almeida-Pereira ◽  
Beatriz de Carvalho Borges ◽  
...  
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Energy Expenditure ◽  
Energy Homeostasis ◽  
Specific Pattern ◽  
Conditional Knockout ◽  
Steroidogenic Factor 1 ◽  
Diet Induced Obesity ◽  
Affect Body Weight

Leptin plays an important role in the protection against diet-induced obesity (DIO) by its actions in ventromedial hypothalamic (VMH) neurons. However, little is known about the intracellular mechanisms involved in these effects. To assess the role of the STAT3 and ERK2 signaling in neurons that express the steroidogenic factor 1 (SF1) in the VMH on energy homeostasis, we used cre-lox technology to generate male and female mice with specific disruption of STAT3 or ERK2 in SF1 neurons of the VMH. We demonstrated that the conditional knockout of STAT3 in SF1 neurons of the VMH did not affect body weight, food intake, energy expenditure and glucose homeostasis in animals on regular chow. However, when challenged with high-fat diet (HFD), loss of STAT3 in SF1 neurons caused a significant increase in body weight, food intake and energy efficiency that was more remarkable in females which also showed a decrease in energy expenditure. In contrast, deletion of ERK2 in SF1 neurons of VMH did not have any impact on energy homeostasis in both regular diet and HFD conditions. In conclusion, STAT3 but not ERK2 signaling in SF1 neurons of VMH plays a crucial role to protect against DIO in a sex-specific pattern.

scholarly journals Selenium Regulates Hypothalamic Control of Energy Metabolism in a Sexually Dimorphic Manner

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1844-1844
Author(s):  
Daniel Torres ◽  
Matthew Pitts ◽  
Lucia Seale ◽  
Ann Hashimoto ◽  
Katlyn An ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Food Intake ◽  
Energy Expenditure ◽  
Glucose Tolerance ◽  
High Fat Diet ◽  
Metabolic Phenotype ◽  
Sexually Dimorphic ◽  
High Fat ◽  
Diet Induced Obesity

Abstract Objectives The trace element selenium (Se) is known mainly for its antioxidant properties and is critical for proper brain function. The role of Se in regulating energy metabolism, and the sexually dimorphic nature of Se functions, however, are underappreciated, and warrant increased attention. Recent work in our lab has highlighted the importance of Se utilization in hypothalamic regulation of energy metabolism. Dietary Se is incorporated into selenoproteins in the form of the unique amino acid selenocysteine (Sec). The objective of this study was to assess the role of selenoproteins in Agouti-related peptide (Agrp)-positive neurons, an orexigenic sub-population of the hypothalamus. Methods We generated mice with Agrp-Cre-driven deletion of selenocysteine tRNA (Trsp-Agrp KO mice), which is essential for Sec incorporation into selenoproteins, thus ablating selenoprotein synthesis in Agrp-positive neurons. The metabolic phenotype of Trsp-Agrp KO mice challenged with a high-fat diet was characterized via glucose tolerance test (i.p. injection) and the use of analytical chambers to measure food intake and respiratory metabolism. Prior to sacrifice, mice were challenged with leptin (i.p. injection) to assess neuronal leptin responsivity via immunohistochemistry and western blot. Brown adipose tissue (BAT) morphology and thermogenic protein expression were also analyzed. Results Female Trsp-Agrp KO mice displayed resistance to diet-induced obesity, which was accompanied by improved glucose tolerance and elevated energy expenditure levels without changes in food intake. Female Trsp-Agrp KO mice also had greater leptin sensitivity and showed signs of elevated BAT thermogenesis. Male Trsp-Agrp KO mice displayed no changes in metabolic phenotype. Conclusions Loss of selenoproteins in Agrp-positive neurons of the hypothalamus promotes energy expenditure and reduces diet-induced obesity in a sexually dimorphic manner, leading to resistance to a high-fat diet in females. Funding Sources This work was funded by grant support from the National Institute of Diabetes and Digestive and Kidney Diseases (MJB) and Ola HAWAII, a grant from the National Institute on Minority Health and Health Disparities.

scholarly journals IL-37 Expression Reduces Lean Body Mass in Mice by Reducing Food Intake

2018 ◽  
Vol 19 (8) ◽  
pp. 2264 ◽  
Author(s):  
Eline Kuipers ◽  
Andrea van Dam ◽  
Dov Ballak ◽  
Ellemiek de Wit ◽  
Charles Dinarello ◽  
...  
Keyword(s):  
Food Intake ◽  
Energy Expenditure ◽  
Lean Body Mass ◽  
Body Mass ◽  
Plasma Lipid ◽  
Metabolic Effects ◽  
Metabolic Complications ◽  
Transgenic Expression ◽  
Reduced Body ◽  
Diet Induced Obesity

The human cytokine interleukin (IL)-37 is an anti-inflammatory member of the IL-1 family of cytokines. Transgenic expression of IL-37 in mice protects them from diet-induced obesity and associated metabolic complications including dyslipidemia, inflammation and insulin resistance. The precise mechanism of action leading to these beneficial metabolic effects is not entirely known. Therefore, we aimed to assess in detail the effect of transgenic IL-37 expression on energy balance, including food intake and energy expenditure. Feeding homozygous IL-37 transgenic mice and wild-type (WT) control mice a high-fat diet (HFD; 45% kcal palm fat) for 6 weeks showed that IL-37 reduced body weight related to a marked decrease in food intake. Subsequent mechanistic studies in mice with heterozygous IL-37 expression versus WT littermates, fed the HFD for 18 weeks, confirmed that IL-37 reduces food intake, which led to a decrease in lean body mass, but did not reduce fat mass and plasma lipid levels or alterations in energy expenditure independent of lean body mass. Taken together, this suggests that IL-37 reduces lean body mass by reducing food intake.

scholarly journals The Epidermal Barrier is Indispensable for Systemic Energy Homeostasis

2020 ◽  
Author(s):  
Vibeke Kruse ◽  
Ditte Neess ◽  
Ann-Britt Marcher ◽  
Mie Rye Wæde ◽  
Julie Vistisen ◽  
...  
Keyword(s):  
Food Intake ◽  
Body Temperature ◽  
Energy Expenditure ◽  
Barrier Function ◽  
Physiological Responses ◽  
Metabolic Phenotype ◽  
Oral Glucose ◽  
Skin Lipid ◽  
Epidermal Barrier ◽  
Diet Induced Obesity

ABSTRACTObjectivesHomeostatic regulation of body temperature is fundamental to mammalian physiology and is controlled by acute and chronic responses of local, endocrine and neuronal regulators. Although the skin is the largest sensory organ of the human body, and plays a fundamental role in regulating body temperature, it is surprising that adaptive alterations in skin functions and morphology only vaguely have been associated with physiological responses to cold stress or sensation of ambient temperatures.MethodsTo unravel the physiological responses to a compromised epidermal barrier in detail we have used animal models with either defects in skin lipid metabolism (ACBP-/- and skin-specific ACBP-/- knockout mice) or defects in skin structural proteins (ma/ma Flgft/ft). The primary objective was to clarify how defects in epidermal barrier function affect 1) energy expenditure by indirect calorimetry, 2) response to high fat feeding and a high oral glucose load and 3) expression of brown-selective gene programs by quantitative PCR in inguinal WAT (iWAT).ResultsWe show that mice with a compromised epidermal barrier function exhibit increased energy expenditure, increased food intake, browning of the iWAT, and resistance to diet-induced obesity. The metabolic phenotype, including browning of the iWAT, is reversed by housing the mice at thermoneutrality (30°C) or by pharmacological β-adrenergic blocking. These findings show that a compromised epidermal barrier induces a β-adrenergic response that increases energy expenditure and browning of the white adipose tissue to maintain a normal body temperature.ConclusionOur findings show that the epidermal barrier plays a key role in maintaining systemic metabolic homeostasis.HighlightsEnergy expenditure is significantly augmented in mice with impaired epidermal barrier.Mice with compromised barrier display increased food intake while maintaining normal bodyweight.Mice with an impaired epidermal barrier are resistant to diet-induced obesity and insulin resistance.Compromised barrier function induces expression of brown-selective gene programs in iWAT.Thermoneutral housing or blocking β-adrenergic signaling prevents induction of brite-selective genes in iWAT and reverses food intake.

scholarly journals STAT3 but Not ERK2 Is a Crucial Mediator Against Diet-Induced Obesity via VMH Neurons

2021 ◽  
Author(s):  
Gabriel Henrique Marques Gonçalves ◽  
Sabrina Mara Tristão ◽  
Rafaella Eduarda Volpi ◽  
Gislaine Almeida-Pereira ◽  
Beatriz de Carvalho Borges ◽  
...  
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Energy Expenditure ◽  
Energy Homeostasis ◽  
Specific Pattern ◽  
Conditional Knockout ◽  
Steroidogenic Factor 1 ◽  
Diet Induced Obesity ◽  
Affect Body Weight

Leptin plays an important role in the protection against diet-induced obesity (DIO) by its actions in ventromedial hypothalamic (VMH) neurons. However, little is known about the intracellular mechanisms involved in these effects. To assess the role of the STAT3 and ERK2 signaling in neurons that express the steroidogenic factor 1 (SF1) in the VMH on energy homeostasis, we used cre-lox technology to generate male and female mice with specific disruption of STAT3 or ERK2 in SF1 neurons of the VMH. We demonstrated that the conditional knockout of STAT3 in SF1 neurons of the VMH did not affect body weight, food intake, energy expenditure and glucose homeostasis in animals on regular chow. However, when challenged with high-fat diet (HFD), loss of STAT3 in SF1 neurons caused a significant increase in body weight, food intake and energy efficiency that was more remarkable in females which also showed a decrease in energy expenditure. In contrast, deletion of ERK2 in SF1 neurons of VMH did not have any impact on energy homeostasis in both regular diet and HFD conditions. In conclusion, STAT3 but not ERK2 signaling in SF1 neurons of VMH plays a crucial role to protect against DIO in a sex-specific pattern.

scholarly journals Susceptibility to diet-induced obesity at thermoneutral conditions is independent of UCP1

2021 ◽  
Author(s):  
Sebastian Dieckmann ◽  
Akim Strohmeyer ◽  
Monja Willershäuser ◽  
Stefanie F. Maurer ◽  
Wolfgang Wurst ◽  
...  
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Energy Expenditure ◽  
Knockout Mice ◽  
Body Weight Gain ◽  
Uncoupling Protein ◽  
Exon 2 ◽  
Diet Induced Obesity ◽  
Brown Adipose ◽  
Knockout Model

Objective Activation of uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) upon cold stimulation leads to substantial increase in energy expenditure to defend body temperature. Increases in energy expenditure after a high caloric food intake, termed diet-induced thermogenesis, are also attributed to BAT. These properties render BAT a potential target to combat diet-induced obesity. However, studies investigating the role of UCP1 to protect against diet-induced obesity are controversial and rely on the phenotyping of a single constitutive UCP1-knockout model. To address this issue, we generated a novel UCP1-knockout model by Cre-mediated deletion of Exon 2 in the UCP1 gene. We studied the effect of constitutive UCP1 knockout on metabolism and the development of diet-induced obesity. Methods UCP1 knockout and wildtype mice were housed at 30°C and fed a control diet for 4-weeks followed by 8-weeks of high-fat diet. Body weight and food intake were monitored continuously over the course of the study and indirect calorimetry was used to determine energy expenditure during both feeding periods. Results Based on Western blot analysis, thermal imaging and noradrenaline test, we confirmed the lack of functional UCP1 in knockout mice. However, body weight gain, food intake and energy expenditure were not affected by deletion of UCP1 gene function during both feeding periods. Conclusion We introduce a novel UCP1-KO mouse enabling the generation of conditional UCP1-knockout mice to scrutinize the contribution of UCP1 to energy metabolism in different cell types or life stages. Our results demonstrate that UCP1 does not protect against diet-induced obesity at thermoneutrality.

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