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Notch intracellular domain overexpression in adipocytes confers lipodystrophy in mice.

Chartoumpekis DV, Palliyaguru DL, Wakabayashi N, Khoo NK, Schoiswohl G, O'Doherty RM, Kensler TW - Mol Metab (2015)

Bottom Line: Gene expression analysis in the adipose tissue depots showed a significant repression of lipogenic (Fasn, Acacb) and adipogenic pathways (C/ebpα, C/ebpβ, Pparγ2, Srebf1).Increased Notch signaling in adipocytes in mice results in blocked expansion of white adipose tissue which leads to ectopic accumulation of lipids and insulin resistance, thus to a lipodystrophic phenotype.These results suggest that further investigation of the role of Notch signaling in adipocytes could lead to the manipulation of this pathway for therapeutic interventions in metabolic disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology & Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.

ABSTRACT

Objective: The Notch family of intermembrane receptors is highly conserved across species and is involved in cell fate and lineage control. Previous in vitro studies have shown that Notch may inhibit adipogenesis. Here we describe the role of Notch in adipose tissue by employing an in vivo murine model which overexpresses Notch in adipose tissue.

Methods: Albino C57BL/6J Rosa(NICD/NICD)::Adipoq-Cre (Ad-NICD) male mice were generated to overexpress the Notch intracellular domain (NICD) specifically in adipocytes. Male Rosa(NICD/NICD) mice were used as controls. Mice were evaluated metabolically at the ages of 1 and 3 months by assessing body weights, serum metabolites, body composition (EchoMRI), glucose tolerance and insulin tolerance. Histological sections of adipose tissue depots as well as of liver were examined. The mRNA expression profile of genes involved in adipogenesis was analyzed by quantitative real-time PCR.

Results: The Ad-NICD mice were heavier with significantly lower body fat mass compared to the controls. Small amounts of white adipose tissue could be seen in the 1-month old Ad-NICD mice, but was almost absent in the 3-months old mice. The Ad-NICD mice also had higher serum levels of glucose, insulin, triglyceride and non-esterified fatty acids. These differences were more prominent in the older (3-months) than in the younger (1-month) mice. The Ad-NICD mice also showed severe insulin resistance along with a steatotic liver. Gene expression analysis in the adipose tissue depots showed a significant repression of lipogenic (Fasn, Acacb) and adipogenic pathways (C/ebpα, C/ebpβ, Pparγ2, Srebf1).

Conclusions: Increased Notch signaling in adipocytes in mice results in blocked expansion of white adipose tissue which leads to ectopic accumulation of lipids and insulin resistance, thus to a lipodystrophic phenotype. These results suggest that further investigation of the role of Notch signaling in adipocytes could lead to the manipulation of this pathway for therapeutic interventions in metabolic disease.

No MeSH data available.


Related in: MedlinePlus

Phenotypic evaluation of the RosaNICD/NICD:: Adipoq-Cre (Ad-NICD) mouse. A. Body weight measurements in 22 day old to 90 day old male mice. Control mice are the RosaNICD/NICD. n = 5 for the control and n = 8 for the Ad-NICD. B. Daily food intake as assessed in single-housed mice (n = 5 for each genotype). C. Daily food intake expressed as grams per gram of body weight (BW). D.Absolute fat mass measurement using Echo-MRI in 1-month old male mice. n = 8 for the control and n = 9 for the Ad-NICD. E. Fat mass measurement using Echo-MRI expressed as percentage of the total body weight (%BW) in 1-month old male mice. n = 8 for the control and n = 9 for the Ad-NICD. F. Absolute fat mass measurement using Echo-MRI in 3-month old male mice. n = 7 for the control and n = 6 for the Ad-NICD. G. Fat mass measurement using Echo-MRI expressed as %BW in 3-month old male mice. n = 7 for the control and n = 6 for the Ad-NICD. H. Absolute lean mass measurement using Echo-MRI in 1-month old male mice. n = 8 for the control and n = 9 for the Ad-NICD. I. Lean mass measurement using Echo-MRI expressed as percentage of the total body weight (%BW) in 1-month old male mice. n = 8 for the control and n = 9 for the Ad-NICD. J. Absolute lean mass measurement using Echo-MRI in 3-month old male mice. n = 7 for the control and n = 6 for the Ad-NICD. K. Lean mass measurement using Echo-MRI expressed as %BW in 3-month old male mice. n = 7 for the control and n = 6 for the Ad-NICD. L. Necropsy photos of the epididymal white adipose tissue (eWAT) in 1-month old mice. Ruler values are in cm. The diagram shows the weight of the eWAT expressed as %BW. n = 8 for the control and n = 9 for the Ad-NICD. M. Representative microscope photos of hematoxylin & eosin stained paraffin embedded sections of epididymal (eWAT) and inguinal (iWAT) white adipose tissue from 1-month old male mice. N. Necropsy photos of interscapular brown adipose tissue (iBAT) from 1-month old male mice. Ruler values are in cm. The diagram shows the weight of the iBAT expressed as %BW. n = 8 for the control and n = 9 for the Ad-NICD. O. Representative microscope photos of hematoxylin & eosin stained paraffin embedded sections of interscapular brown adipose tissue (iBAT) from 1-month old male mice. Data show means ± SEM, *p < 0.05.
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fig1: Phenotypic evaluation of the RosaNICD/NICD:: Adipoq-Cre (Ad-NICD) mouse. A. Body weight measurements in 22 day old to 90 day old male mice. Control mice are the RosaNICD/NICD. n = 5 for the control and n = 8 for the Ad-NICD. B. Daily food intake as assessed in single-housed mice (n = 5 for each genotype). C. Daily food intake expressed as grams per gram of body weight (BW). D.Absolute fat mass measurement using Echo-MRI in 1-month old male mice. n = 8 for the control and n = 9 for the Ad-NICD. E. Fat mass measurement using Echo-MRI expressed as percentage of the total body weight (%BW) in 1-month old male mice. n = 8 for the control and n = 9 for the Ad-NICD. F. Absolute fat mass measurement using Echo-MRI in 3-month old male mice. n = 7 for the control and n = 6 for the Ad-NICD. G. Fat mass measurement using Echo-MRI expressed as %BW in 3-month old male mice. n = 7 for the control and n = 6 for the Ad-NICD. H. Absolute lean mass measurement using Echo-MRI in 1-month old male mice. n = 8 for the control and n = 9 for the Ad-NICD. I. Lean mass measurement using Echo-MRI expressed as percentage of the total body weight (%BW) in 1-month old male mice. n = 8 for the control and n = 9 for the Ad-NICD. J. Absolute lean mass measurement using Echo-MRI in 3-month old male mice. n = 7 for the control and n = 6 for the Ad-NICD. K. Lean mass measurement using Echo-MRI expressed as %BW in 3-month old male mice. n = 7 for the control and n = 6 for the Ad-NICD. L. Necropsy photos of the epididymal white adipose tissue (eWAT) in 1-month old mice. Ruler values are in cm. The diagram shows the weight of the eWAT expressed as %BW. n = 8 for the control and n = 9 for the Ad-NICD. M. Representative microscope photos of hematoxylin & eosin stained paraffin embedded sections of epididymal (eWAT) and inguinal (iWAT) white adipose tissue from 1-month old male mice. N. Necropsy photos of interscapular brown adipose tissue (iBAT) from 1-month old male mice. Ruler values are in cm. The diagram shows the weight of the iBAT expressed as %BW. n = 8 for the control and n = 9 for the Ad-NICD. O. Representative microscope photos of hematoxylin & eosin stained paraffin embedded sections of interscapular brown adipose tissue (iBAT) from 1-month old male mice. Data show means ± SEM, *p < 0.05.

Mentions: Comparisons of the body weights of male Ad-NICD mice with their RosaNICD/NICD (control) counterparts indicate that they weigh significantly more at weaning (22 days of age) and that this difference in weight is accentuated over time (Figure 1A). The absolute amount of food consumption was higher in the Ad-NICD mice (Figure 1B), but when normalized to body weight, no significant difference was observed (Figure 1C). However, the absolute amounts of body fat were significantly (p < 0.05) lower in the Ad-NICD mice at 1-month of age (1.30 g vs 2.22 g in controls) (Figure 1D) and in 3-month old mice (2.97 g vs 5.87 g in controls) (Figure 1F), as measured by EchoMRI. The fat mass to body weight ratio was significantly lower in the Ad-NICD mice both at 1 and 3 months of age (Figure 1E,G). On the other hand, the Ad-NICD mice had increased absolute lean body mass at 1 and 3 months of age (Figure 1H,J) while the lean mass as % of body weight showed little difference (Figure 1I,K).


Notch intracellular domain overexpression in adipocytes confers lipodystrophy in mice.

Chartoumpekis DV, Palliyaguru DL, Wakabayashi N, Khoo NK, Schoiswohl G, O'Doherty RM, Kensler TW - Mol Metab (2015)

Phenotypic evaluation of the RosaNICD/NICD:: Adipoq-Cre (Ad-NICD) mouse. A. Body weight measurements in 22 day old to 90 day old male mice. Control mice are the RosaNICD/NICD. n = 5 for the control and n = 8 for the Ad-NICD. B. Daily food intake as assessed in single-housed mice (n = 5 for each genotype). C. Daily food intake expressed as grams per gram of body weight (BW). D.Absolute fat mass measurement using Echo-MRI in 1-month old male mice. n = 8 for the control and n = 9 for the Ad-NICD. E. Fat mass measurement using Echo-MRI expressed as percentage of the total body weight (%BW) in 1-month old male mice. n = 8 for the control and n = 9 for the Ad-NICD. F. Absolute fat mass measurement using Echo-MRI in 3-month old male mice. n = 7 for the control and n = 6 for the Ad-NICD. G. Fat mass measurement using Echo-MRI expressed as %BW in 3-month old male mice. n = 7 for the control and n = 6 for the Ad-NICD. H. Absolute lean mass measurement using Echo-MRI in 1-month old male mice. n = 8 for the control and n = 9 for the Ad-NICD. I. Lean mass measurement using Echo-MRI expressed as percentage of the total body weight (%BW) in 1-month old male mice. n = 8 for the control and n = 9 for the Ad-NICD. J. Absolute lean mass measurement using Echo-MRI in 3-month old male mice. n = 7 for the control and n = 6 for the Ad-NICD. K. Lean mass measurement using Echo-MRI expressed as %BW in 3-month old male mice. n = 7 for the control and n = 6 for the Ad-NICD. L. Necropsy photos of the epididymal white adipose tissue (eWAT) in 1-month old mice. Ruler values are in cm. The diagram shows the weight of the eWAT expressed as %BW. n = 8 for the control and n = 9 for the Ad-NICD. M. Representative microscope photos of hematoxylin & eosin stained paraffin embedded sections of epididymal (eWAT) and inguinal (iWAT) white adipose tissue from 1-month old male mice. N. Necropsy photos of interscapular brown adipose tissue (iBAT) from 1-month old male mice. Ruler values are in cm. The diagram shows the weight of the iBAT expressed as %BW. n = 8 for the control and n = 9 for the Ad-NICD. O. Representative microscope photos of hematoxylin & eosin stained paraffin embedded sections of interscapular brown adipose tissue (iBAT) from 1-month old male mice. Data show means ± SEM, *p < 0.05.
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fig1: Phenotypic evaluation of the RosaNICD/NICD:: Adipoq-Cre (Ad-NICD) mouse. A. Body weight measurements in 22 day old to 90 day old male mice. Control mice are the RosaNICD/NICD. n = 5 for the control and n = 8 for the Ad-NICD. B. Daily food intake as assessed in single-housed mice (n = 5 for each genotype). C. Daily food intake expressed as grams per gram of body weight (BW). D.Absolute fat mass measurement using Echo-MRI in 1-month old male mice. n = 8 for the control and n = 9 for the Ad-NICD. E. Fat mass measurement using Echo-MRI expressed as percentage of the total body weight (%BW) in 1-month old male mice. n = 8 for the control and n = 9 for the Ad-NICD. F. Absolute fat mass measurement using Echo-MRI in 3-month old male mice. n = 7 for the control and n = 6 for the Ad-NICD. G. Fat mass measurement using Echo-MRI expressed as %BW in 3-month old male mice. n = 7 for the control and n = 6 for the Ad-NICD. H. Absolute lean mass measurement using Echo-MRI in 1-month old male mice. n = 8 for the control and n = 9 for the Ad-NICD. I. Lean mass measurement using Echo-MRI expressed as percentage of the total body weight (%BW) in 1-month old male mice. n = 8 for the control and n = 9 for the Ad-NICD. J. Absolute lean mass measurement using Echo-MRI in 3-month old male mice. n = 7 for the control and n = 6 for the Ad-NICD. K. Lean mass measurement using Echo-MRI expressed as %BW in 3-month old male mice. n = 7 for the control and n = 6 for the Ad-NICD. L. Necropsy photos of the epididymal white adipose tissue (eWAT) in 1-month old mice. Ruler values are in cm. The diagram shows the weight of the eWAT expressed as %BW. n = 8 for the control and n = 9 for the Ad-NICD. M. Representative microscope photos of hematoxylin & eosin stained paraffin embedded sections of epididymal (eWAT) and inguinal (iWAT) white adipose tissue from 1-month old male mice. N. Necropsy photos of interscapular brown adipose tissue (iBAT) from 1-month old male mice. Ruler values are in cm. The diagram shows the weight of the iBAT expressed as %BW. n = 8 for the control and n = 9 for the Ad-NICD. O. Representative microscope photos of hematoxylin & eosin stained paraffin embedded sections of interscapular brown adipose tissue (iBAT) from 1-month old male mice. Data show means ± SEM, *p < 0.05.
Mentions: Comparisons of the body weights of male Ad-NICD mice with their RosaNICD/NICD (control) counterparts indicate that they weigh significantly more at weaning (22 days of age) and that this difference in weight is accentuated over time (Figure 1A). The absolute amount of food consumption was higher in the Ad-NICD mice (Figure 1B), but when normalized to body weight, no significant difference was observed (Figure 1C). However, the absolute amounts of body fat were significantly (p < 0.05) lower in the Ad-NICD mice at 1-month of age (1.30 g vs 2.22 g in controls) (Figure 1D) and in 3-month old mice (2.97 g vs 5.87 g in controls) (Figure 1F), as measured by EchoMRI. The fat mass to body weight ratio was significantly lower in the Ad-NICD mice both at 1 and 3 months of age (Figure 1E,G). On the other hand, the Ad-NICD mice had increased absolute lean body mass at 1 and 3 months of age (Figure 1H,J) while the lean mass as % of body weight showed little difference (Figure 1I,K).

Bottom Line: Gene expression analysis in the adipose tissue depots showed a significant repression of lipogenic (Fasn, Acacb) and adipogenic pathways (C/ebpα, C/ebpβ, Pparγ2, Srebf1).Increased Notch signaling in adipocytes in mice results in blocked expansion of white adipose tissue which leads to ectopic accumulation of lipids and insulin resistance, thus to a lipodystrophic phenotype.These results suggest that further investigation of the role of Notch signaling in adipocytes could lead to the manipulation of this pathway for therapeutic interventions in metabolic disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology & Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.

ABSTRACT

Objective: The Notch family of intermembrane receptors is highly conserved across species and is involved in cell fate and lineage control. Previous in vitro studies have shown that Notch may inhibit adipogenesis. Here we describe the role of Notch in adipose tissue by employing an in vivo murine model which overexpresses Notch in adipose tissue.

Methods: Albino C57BL/6J Rosa(NICD/NICD)::Adipoq-Cre (Ad-NICD) male mice were generated to overexpress the Notch intracellular domain (NICD) specifically in adipocytes. Male Rosa(NICD/NICD) mice were used as controls. Mice were evaluated metabolically at the ages of 1 and 3 months by assessing body weights, serum metabolites, body composition (EchoMRI), glucose tolerance and insulin tolerance. Histological sections of adipose tissue depots as well as of liver were examined. The mRNA expression profile of genes involved in adipogenesis was analyzed by quantitative real-time PCR.

Results: The Ad-NICD mice were heavier with significantly lower body fat mass compared to the controls. Small amounts of white adipose tissue could be seen in the 1-month old Ad-NICD mice, but was almost absent in the 3-months old mice. The Ad-NICD mice also had higher serum levels of glucose, insulin, triglyceride and non-esterified fatty acids. These differences were more prominent in the older (3-months) than in the younger (1-month) mice. The Ad-NICD mice also showed severe insulin resistance along with a steatotic liver. Gene expression analysis in the adipose tissue depots showed a significant repression of lipogenic (Fasn, Acacb) and adipogenic pathways (C/ebpα, C/ebpβ, Pparγ2, Srebf1).

Conclusions: Increased Notch signaling in adipocytes in mice results in blocked expansion of white adipose tissue which leads to ectopic accumulation of lipids and insulin resistance, thus to a lipodystrophic phenotype. These results suggest that further investigation of the role of Notch signaling in adipocytes could lead to the manipulation of this pathway for therapeutic interventions in metabolic disease.

No MeSH data available.


Related in: MedlinePlus