Mct8-Deficient Mice Have Increased Energy Expenditure and Reduced Fat Mass That Is Abrogated by Normalization of Serum T3 Levels

Children with monocarboxylate transporter 8 (MCT8) deficiency lose weight, even when adequately nourished. Changes in serum markers of thyroid hormone (TH) action compatible with thyrotoxicosis suggested that this might be due to T3 excess in peripheral tissues. Mct8-deficient mice (Mct8KO) replicate the human thyroid phenotype and are thus suitable for metabolic studies so far unavailable in humans. In the current work, compared with wild-type (Wt) mice, Mct8KO mice were leaner due to reduced fat mass. They tended to use more carbohydrates and fewer lipids during the dark phase. Mct8KO mice had increased total energy expenditure (TEE) and food and water intake, with normal total activity, indicating hypermetabolism. To determine whether this is due to the high serum T3, we studied mice deficient in both Mct8 and deiodinase 1 (Mct8D1KO) with serum T3 similar to Wt mice and Wt mice given L-T3 to raise their serum T3 to the level of Mct8KO mice. Contrary to Mct8KO, Mct8D1KO mice had similar fat mass, TEE, and food intake as their D1KO littermates, whereas T3-treated Wt mice showed increased food intake and TEE, similar to Mct8KO mice. In skeletal muscle, Mct8KO mice had increased T3 content and TH action and increased glucose metabolism, which improved in Mct8D1KO mice. These studies indicate that the high serum T3 in MCT8 deficiency increases the TEE and fails to maintain weight despite adequate calorie intake. This is mediated by tissues that are not predominantly MCT8 dependent for TH transport, including skeletal muscle. Normalizing serum T3 level by deleting deiodinase 1 corrects body composition and the metabolic alterations caused by the MCT8 deficiency.

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Mct8 Deficient Mice Have Increased Energy Expenditure and Reduced Fat Mass That Is Abrogated by Deiodinase 1 Deletion

10.1210/endo-meetings.2011.part2.p16.p1-658 ◽

2011 ◽

pp. P1-658-P1-658

Author(s):

Caterina Di Cosmo ◽

Xiao-Hui Liao ◽

Alexandra M Dumitrescu ◽

Honggang Ye ◽

Roy E Weiss ◽

...

Keyword(s):

Energy Expenditure ◽

Fat Mass ◽

Reduced Fat ◽

Deficient Mice

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The Thyroid Hormone Analog DITPA Ameliorates Metabolic Parameters of Male Mice With Mct8 Deficiency

Endocrinology ◽

10.1210/en.2015-1234 ◽

2015 ◽

Vol 156 (11) ◽

pp. 3889-3894 ◽

Cited By ~ 17

Author(s):

Alfonso Massimiliano Ferrara ◽

Xiao-Hui Liao ◽

Honggang Ye ◽

Roy E. Weiss ◽

Alexandra M. Dumitrescu ◽

...

Keyword(s):

Thyroid Hormone ◽

Energy Expenditure ◽

Target Genes ◽

High Serum ◽

Metabolic Parameters ◽

Monocarboxylate Transporter ◽

Hormone Analog ◽

Serum T3 ◽

Mct8 Deficiency ◽

The Brain

Mutations in the gene encoding the thyroid hormone (TH) transporter, monocarboxylate transporter 8 (MCT8), cause mental retardation in humans associated with a specific thyroid hormone phenotype manifesting high serum T3 and low T4 and rT3 levels. Moreover, these patients have failure to thrive, and physiological changes compatible with thyrotoxicosis. Recent studies in Mct8-deficient (Mct8KO) mice revealed that the high serum T3 causes increased energy expenditure. The TH analog, diiodothyropropionic acid (DITPA), enters cells independently of Mct8 transport and shows thyromimetic action but with a lower metabolic activity than TH. In this study DITPA was given daily ip to adult Mct8KO mice to determine its effect on thyroid tests in serum and metabolism (total energy expenditure, respiratory exchange rate, and food and water intake). In addition, we measured the expression of TH-responsive genes in the brain, liver, and muscles to assess the thyromimetic effects of DITPA. Administration of 0.3 mg DITPA per 100 g body weight to Mct8KO mice brought serum T3 levels and the metabolic parameters studied to levels observed in untreated Wt animals. Analysis of TH target genes revealed amelioration of the thyrotoxic state in liver, somewhat in the soleus, but there was no amelioration of the brain hypothyroidism. In conclusion, at the dose used, DITPA mainly ameliorated the hypermetabolism of Mct8KO mice. This thyroid hormone analog is suitable for the treatment of the hypermetabolism in patients with MCT8 deficiency, as suggested in limited preliminary human trials.

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Increased energy expenditure and leptin sensitivity account for low fat mass in myostatin-deficient mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00656.2010 ◽

2011 ◽

Vol 300 (6) ◽

pp. E1031-E1037 ◽

Cited By ~ 29

Author(s):

Sun Ju Choi ◽

Zipora Yablonka-Reuveni ◽

Karl J. Kaiyala ◽

Kayoko Ogimoto ◽

Michael W. Schwartz ◽

...

Keyword(s):

Food Intake ◽

Energy Expenditure ◽

Body Mass ◽

Body Fat ◽

Fat Mass ◽

Body Fat Mass ◽

Low Fat ◽

Total Body Mass ◽

Leptin Sensitivity ◽

Deficient Mice

Myostatin deficiency causes dramatically increased skeletal muscle mass and reduced fat mass. Previously, myostatin-deficient mice were reported to have unexpectedly low total energy expenditure (EE) after normalizing to body mass, and thus, a metabolic cause for low fat mass was discounted. To clarify how myostatin deficiency affects the control of body fat mass and energy balance, we compared rates of oxygen consumption, body composition, and food intake in young myostatin-deficient mice relative to wild-type (WT) and heterozygous (HET) controls. We report that after adjusting for total body mass using regression analysis, young myostatin-deficient mice display significantly increased EE relative to both WT (+0.81 ± 0.28 kcal/day, P = 0.004) and HET controls (+0.92 ± 0.31 kcal/day, P = 0.005). Since food intake was not different between groups, increased EE likely accounts for the reduced body fat mass (KO: 8.8 ± 1.1% vs. WT: 14.5 ± 1.3%, P = 0.003) and circulating leptin levels (KO: 0.7 ± 0.2 ng/ml vs. WT: 1.9 ± 0.3 ng/ml, P = 0.008). Interestingly, the observed increase in adjusted EE in myostatin-deficient mice occurred despite dramatically reduced ambulatory activity levels (−50% vs. WT, P < 0.05). The absence of hyperphagia together with increased EE in myostatin-deficient mice suggests that increased leptin sensitivity may contribute to their lean phenotype. Indeed, leptin-induced anorexia (KO: −17 ± 1.2% vs. WT: −5 ± 0.3%) and weight loss (KO: −2.2 ± 0.2 g vs. WT: −1.6 ± 0.1, P < 0.05) were increased in myostatin-deficient mice compared with WT controls. We conclude that increased EE, together with increased leptin sensitivity, contributes to low fat mass in mice lacking myostatin.

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Decreased Fat Mass in Interleukin-1 Receptor Antagonist-Deficient Mice: Impact on Adipogenesis, Food Intake, and Energy Expenditure

Diabetes ◽

10.2337/diabetes.54.12.3503 ◽

2005 ◽

Vol 54 (12) ◽

pp. 3503-3509 ◽

Cited By ~ 77

Author(s):

E. Somm ◽

E. Henrichot ◽

A. Pernin ◽

C. E. Juge-Aubry ◽

P. Muzzin ◽

...

Keyword(s):

Food Intake ◽

Energy Expenditure ◽

Receptor Antagonist ◽

Fat Mass ◽

Interleukin 1 ◽

Interleukin 1 Receptor Antagonist ◽

Deficient Mice

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Minimal impact of age and housing temperature on the metabolic phenotype of Acc2−/− mice

Journal of Endocrinology ◽

10.1530/joe-15-0444 ◽

2015 ◽

Vol 228 (3) ◽

pp. 127-134 ◽

Cited By ~ 6

Author(s):

Amanda E Brandon ◽

Ella Stuart ◽

Simon J Leslie ◽

Kyle L Hoehn ◽

David E James ◽

...

Keyword(s):

Skeletal Muscle ◽

Body Composition ◽

Energy Expenditure ◽

Glucose Tolerance ◽

Fat Mass ◽

Knockout Mice ◽

Muscle Glycogen ◽

Insulin Action ◽

Metabolic Phenotype ◽

Whole Body

An important regulator of fatty acid oxidation (FAO) is the allosteric inhibition of CPT-1 by malonyl-CoA produced by the enzyme acetyl-CoA carboxylase 2 (ACC2). Initial studies suggested that deletion of Acc2 (Acacb) increased fat oxidation and reduced adipose tissue mass but in an independently generated strain of Acc2 knockout mice we observed increased whole-body and skeletal muscle FAO and a compensatory increase in muscle glycogen stores without changes in glucose tolerance, energy expenditure or fat mass in young mice (12–16 weeks). The aim of the present study was to determine whether there was any effect of age or housing at thermoneutrality (29 °C; which reduces total energy expenditure) on the phenotype of Acc2 knockout mice. At 42–54 weeks of age, male WT and Acc2−/− mice had similar body weight, fat mass, muscle triglyceride content and glucose tolerance. Consistent with younger Acc2−/− mice, aged Acc2−/− mice showed increased whole-body FAO (24 h average respiratory exchange ratio=0.95±0.02 and 0.92±0.02 for WT and Acc2−/− mice respectively, P<0.05) and skeletal muscle glycogen content (+60%, P<0.05) without any detectable change in whole-body energy expenditure. Hyperinsulinaemic–euglycaemic clamp studies revealed no difference in insulin action between groups with similar glucose infusion rates and tissue glucose uptake. Housing Acc2−/− mice at 29 °C did not alter body composition, glucose tolerance or the effects of fat feeding compared with WT mice. These results confirm that manipulation of Acc2 may alter FAO in mice, but this has little impact on body composition or insulin action.

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1-Sarcosine-angiotensin II infusion effects on food intake, weight loss, energy expenditure, and skeletal muscle UCP3 gene expression in a rat model

Journal of Cachexia Sarcopenia and Muscle ◽

10.1007/s13539-014-0133-2 ◽

2014 ◽

Vol 5 (3) ◽

pp. 239-246 ◽

Cited By ~ 10

Author(s):

S. A. Cichello ◽

R. S. Weisinger ◽

J. Schuijers ◽

M. Jois

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Weight Loss ◽

Angiotensin Ii ◽

Food Intake ◽

Energy Expenditure ◽

Rat Model ◽

Ucp3 Gene

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Murine neuronatin deficiency is associated with a hypervariable food intake and bimodal obesity

Scientific Reports ◽

10.1038/s41598-021-96278-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Irene Cimino ◽

Debra Rimmington ◽

Y. C. Loraine Tung ◽

Katherine Lawler ◽

Pierre Larraufie ◽

...

Keyword(s):

Body Weight ◽

Energy Balance ◽

Food Intake ◽

Energy Expenditure ◽

Positive Energy ◽

Chow Diet ◽

Chromatin Regulator ◽

Positive Energy Balance ◽

The Impact ◽

Deficient Mice

AbstractNeuronatin (Nnat) has previously been reported to be part of a network of imprinted genes downstream of the chromatin regulator Trim28. Disruption of Trim28 or of members of this network, including neuronatin, results in an unusual phenotype of a bimodal body weight. To better characterise this variability, we examined the key contributors to energy balance in Nnat+/−p mice that carry a paternal null allele and do not express Nnat. Consistent with our previous studies, Nnat deficient mice on chow diet displayed a bimodal body weight phenotype with more than 30% of Nnat+/−p mice developing obesity. In response to both a 45% high fat diet and exposure to thermoneutrality (30 °C) Nnat deficient mice maintained the hypervariable body weight phenotype. Within a calorimetry system, food intake in Nnat+/−p mice was hypervariable, with some mice consuming more than twice the intake seen in wild type littermates. A hyperphagic response was also seen in Nnat+/−p mice in a second, non-home cage environment. An expected correlation between body weight and energy expenditure was seen, but corrections for the effects of positive energy balance and body weight greatly diminished the effect of neuronatin deficiency on energy expenditure. Male and female Nnat+/−p mice displayed subtle distinctions in the degree of variance body weight phenotype and food intake and further sexual dimorphism was reflected in different patterns of hypothalamic gene expression in Nnat+/−p mice. Loss of the imprinted gene Nnat is associated with a highly variable food intake, with the impact of this phenotype varying between genetically identical individuals.

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Shift in metabolic fuel in acylation-stimulating protein-deficient mice following a high-fat diet

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00689.2007 ◽

2008 ◽

Vol 294 (6) ◽

pp. E1051-E1059 ◽

Cited By ~ 23

Author(s):

Christian Roy ◽

Sabina Paglialunga ◽

Alexandre Fisette ◽

Patrick Schrauwen ◽

Esther Moonen-Kornips ◽

...

Keyword(s):

Skeletal Muscle ◽

Fatty Acid ◽

Energy Expenditure ◽

High Fat Diet ◽

Ex Vivo ◽

Direct Result ◽

Acid Oxidation ◽

High Fat ◽

Metabolic Potential ◽

Deficient Mice

ASP-deficient mice (C3 KO) have delayed postprandial TG clearance, are hyperphagic, and display increased energy expenditure. Markers of carbohydrate and fatty acid metabolism in the skeletal muscle and heart were examined to evaluate the mechanism. On a high-fat diet, compared with wild-type mice, C3 KO mice have increased energy expenditure, decreased RQ, lower ex vivo glucose oxidation (−39%, P = 0.018), and higher ex vivo fatty acid oxidation (+68%, P = 0.019). They have lower muscle glycogen content (−25%, P < 0.05) and lower activities for the glycolytic enzymes glycogen phosphorylase (−31%, P = 0.005), hexokinase (−43%, P = 0.007), phosphofructokinase (−51%, P < 0.0001), and GAPDH (−15%, P = 0.04). Analysis of mitochondrial enzyme activities revealed that hydroxyacyl-coenzyme A dehydrogenase was higher (+25%, P = 0.004) in C3 KO mice. Furthermore, Western blot analysis of muscle revealed significantly higher fatty acid transporter CD36 (+40%, P = 0.006) and cytochrome c (a marker of mitochondrial content; +69%, P = 0.034) levels in C3 KO mice, whereas the activity of AMP kinase was lower (−48%, P = 0.003). Overall, these results demonstrate a shift in the metabolic potential of skeletal muscle toward increased fatty acid utilization. Whether this is 1) a consequence of decreased adipose tissue storage with repartitioning toward muscle or 2) a direct result of the absence of ASP interaction with the receptor C5L2 in muscle remains to be determined. However, these in vivo data suggest that ASP inhibition could be a potentially viable approach in correcting muscle metabolic dysfunction in obesity.

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