Reduced fat oxidation in hypertrophied hearts coincides with a shift of carnitine palmitoyl trans... more Reduced fat oxidation in hypertrophied hearts coincides with a shift of carnitine palmitoyl transferase I from muscle to increased liver isoforms. Acutely increased carnitine palmitoyl transferase I in normal rodent hearts has been shown to recapitulate the reduced fat oxidation and elevated atrial natriuretic peptide message of cardiac hypertrophy. Because of the potential for reduced fat oxidation to affect cardiac atrial natriuretic peptide, and thus, induce adipose lipolysis, we studied peripheral and systemic metabolism in male C57BL/6 mice model of transverse aortic constriction in which left ventricular hypertrophy occurred by 2 weeks without functional decline until 16 weeks (ejection fraction, -45.6%; fractional shortening, -22.6%). We report the first evidence for initially improved glucose tolerance and insulin sensitivity in response to 2 weeks transverse aortic constriction versus sham, linked to enhanced insulin signaling in liver and visceral adipose tissue (epididyma...
Journal of endocrinological investigation, Jan 21, 2016
To evaluate the association of galectin-3 (Gal3) with obesity and inflammatory status in a cohort... more To evaluate the association of galectin-3 (Gal3) with obesity and inflammatory status in a cohort of metabolically healthy, predominantly African-American women with varying cardiovascular disease (CVD) risk as determined by CRP levels. We assessed the association between BMI and serum levels of Gal3, IL-6, CRP, and adiponectin in metabolically healthy women (N = 97) to determine the overall association between Gal3, obesity, and inflammation in groups at different CVD risk. Obese women had significantly higher serum Gal3 compared to non-obese participants (P = 0.0016), although Gal3 levels were comparable among different classes of obesity. BMI (R (2) = 0.1406, P = 0.0013), IL-6 (R (2) = 0.0689, P = 0.035), and CRP (R (2) = 0.0468, P = 0.0419), but not adiponectin, positively predicted the variance of Gal3 levels in the total study population. However, the predicting effect of BMI (R (2) = 0.2923, P = 0.0125) and inflammation (R (2) = 0.3138, P = 0.038) on Gal3 was only present in ...
Insulin signaling plays pivotal roles in the development and metabolism of many tissues and cell ... more Insulin signaling plays pivotal roles in the development and metabolism of many tissues and cell types. A previous study demonstrated that ablation of insulin receptor (IR) with aP2-Cre markedly reduced adipose tissues mass and protected mice from obesity. However, multiple studies have demonstrated widespread non-adipocyte recombination of floxed alleles in aP2-Cre mice. These findings underscore the need to re-evaluate the role of IR in adipocyte and systemic metabolism with a more adipose tissue-specific Cre mouse line. We generated and phenotyped a new adipose tissue-specific IR mouse model using the adipose tissue-specific Adipoq-Cre line. Here we show that the Adipoq-Cre-mediated IR KO in mice leads to lipodystrophy and metabolic dysfunction, which is in stark contrast to the previous study. In contrast to white adipocytes, absence of insulin signaling does not affect development of marrow and brown adipocytes, but instead is required for lipid accumulation particularly for the marrow adipocytes. Lipodystrophic IR KO mice have profound insulin resistance, hyperglycemia, organomegaly, and impaired adipokine secretion. Our results demonstrate differential roles for insulin signaling for white, brown, and marrow adipocyte development and metabolic regulation.
Obesity and type 2 diabetes are associated with increased production of Galectin-3 (Gal-3), a pro... more Obesity and type 2 diabetes are associated with increased production of Galectin-3 (Gal-3), a protein that modulates inflammation and clearance of glucose adducts. We used Lean and Diet-induced Obese (DIO) WT and Gal-3 KO mice to investigate the role of Gal-3 in modulation of adiposity, glucose metabolism and inflammation. Deficiency of Gal-3 lead to age-dependent development of excess adiposity and systemic inflammation, as indicated by elevated production of acutephase proteins, number of circulating pro-inflammatory Ly6C high monocytes and development of neutrophilia, microcytic anemia and thrombocytosis in 20-week-old Lean and DIO male Gal-3 KO mice. This was associated with impaired fasting glucose, heightened response to a glucose tolerance test and reduced adipose tissue expression of adiponectin, Gal-12, ATGL and PPARc, in the presence of maintained insulin sensitivity and hepatic expression of gluconeogenic enzymes in 20week-old Gal-3 KO mice compared to their diet-matched WT controls. Expression of PGC-1a and FGF-21 in the liver of Lean Gal-3 KO mice was comparable to that observed in DIO animals. Impaired fasting glucose and altered responsiveness to a glucose load preceded development of excess adiposity and systemic inflammation, as demonstrated in 12-week-old Gal-3 KO mice. Finally, a role for the microflora in mediating the fasting hyperglycemia, but not the excessive response to a glucose load, of 12-week-old Gal-3 KO mice was demonstrated by administration of antibiotics. In conclusion, Gal-3 is an important modulator of glucose metabolism, adiposity and inflammation. Citation: Pang J, Rhodes DH, Pini M, Akasheh RT, Castellanos KJ et al. (2013) Increased Adiposity, Dysregulated Glucose Metabolism and Systemic Inflammation in Galectin-3 KO Mice. PLoS ONE 8(2): e57915.
Production of Annexin A1 (ANXA1), a protein that mediates the anti-inflammatory action of glucoco... more Production of Annexin A1 (ANXA1), a protein that mediates the anti-inflammatory action of glucocorticoids, is altered in obesity, but its role in modulation of adiposity has not yet been investigated. The objective of this study was to investigate modulation of ANXA1 in adipose tissue in murine models of obesity and to study the involvement of ANXA1 in diet-induced obesity in mice. Significant induction of ANXA1 mRNA was observed in adipose tissue of both C57BL6 and Balb/c mice with high fat diet (HFD)-induced obesity versus mice on chow diet. Upregulation of ANXA1 mRNA was independent of leptin or IL-6, as demonstrated by use of leptin-deficient ob/ob mice and IL-6 KO mice. Compared to WT mice, female Balb/c ANXA1 KO mice on HFD had increased adiposity, as indicated by significantly elevated body weight, fat mass, leptin levels, and adipocyte size. Whereas Balb/c WT mice upregulated expression of enzymes involved in the lipolytic pathway in response to HFD, this response was absent in ANXA1 KO mice. A significant increase in fasting glucose and insulin levels as well as development of insulin resistance was observed in ANXA1 KO mice on HFD compared to WT mice. Elevated plasma corticosterone levels and blunted downregulation of 11-beta hydroxysteroid dehydrogenase type 1 in adipose tissue was observed in ANXA1 KO mice compared to diet-matched WT mice. However, no differences between WT and KO mice on either chow or HFD were observed in expression of markers of adipose tissue inflammation. These data indicate that ANXA1 is an important modulator of adiposity in mice, with female ANXA1 KO mice on Balb/c background being more susceptible to weight gain and diet-induced insulin resistance compared to WT mice, without significant changes in inflammation.
Reduced fat oxidation in hypertrophied hearts coincides with a shift of carnitine palmitoyl trans... more Reduced fat oxidation in hypertrophied hearts coincides with a shift of carnitine palmitoyl transferase I from muscle to increased liver isoforms. Acutely increased carnitine palmitoyl transferase I in normal rodent hearts has been shown to recapitulate the reduced fat oxidation and elevated atrial natriuretic peptide message of cardiac hypertrophy. Because of the potential for reduced fat oxidation to affect cardiac atrial natriuretic peptide, and thus, induce adipose lipolysis, we studied peripheral and systemic metabolism in male C57BL/6 mice model of transverse aortic constriction in which left ventricular hypertrophy occurred by 2 weeks without functional decline until 16 weeks (ejection fraction, -45.6%; fractional shortening, -22.6%). We report the first evidence for initially improved glucose tolerance and insulin sensitivity in response to 2 weeks transverse aortic constriction versus sham, linked to enhanced insulin signaling in liver and visceral adipose tissue (epididyma...
Journal of endocrinological investigation, Jan 21, 2016
To evaluate the association of galectin-3 (Gal3) with obesity and inflammatory status in a cohort... more To evaluate the association of galectin-3 (Gal3) with obesity and inflammatory status in a cohort of metabolically healthy, predominantly African-American women with varying cardiovascular disease (CVD) risk as determined by CRP levels. We assessed the association between BMI and serum levels of Gal3, IL-6, CRP, and adiponectin in metabolically healthy women (N = 97) to determine the overall association between Gal3, obesity, and inflammation in groups at different CVD risk. Obese women had significantly higher serum Gal3 compared to non-obese participants (P = 0.0016), although Gal3 levels were comparable among different classes of obesity. BMI (R (2) = 0.1406, P = 0.0013), IL-6 (R (2) = 0.0689, P = 0.035), and CRP (R (2) = 0.0468, P = 0.0419), but not adiponectin, positively predicted the variance of Gal3 levels in the total study population. However, the predicting effect of BMI (R (2) = 0.2923, P = 0.0125) and inflammation (R (2) = 0.3138, P = 0.038) on Gal3 was only present in ...
Insulin signaling plays pivotal roles in the development and metabolism of many tissues and cell ... more Insulin signaling plays pivotal roles in the development and metabolism of many tissues and cell types. A previous study demonstrated that ablation of insulin receptor (IR) with aP2-Cre markedly reduced adipose tissues mass and protected mice from obesity. However, multiple studies have demonstrated widespread non-adipocyte recombination of floxed alleles in aP2-Cre mice. These findings underscore the need to re-evaluate the role of IR in adipocyte and systemic metabolism with a more adipose tissue-specific Cre mouse line. We generated and phenotyped a new adipose tissue-specific IR mouse model using the adipose tissue-specific Adipoq-Cre line. Here we show that the Adipoq-Cre-mediated IR KO in mice leads to lipodystrophy and metabolic dysfunction, which is in stark contrast to the previous study. In contrast to white adipocytes, absence of insulin signaling does not affect development of marrow and brown adipocytes, but instead is required for lipid accumulation particularly for the marrow adipocytes. Lipodystrophic IR KO mice have profound insulin resistance, hyperglycemia, organomegaly, and impaired adipokine secretion. Our results demonstrate differential roles for insulin signaling for white, brown, and marrow adipocyte development and metabolic regulation.
Obesity and type 2 diabetes are associated with increased production of Galectin-3 (Gal-3), a pro... more Obesity and type 2 diabetes are associated with increased production of Galectin-3 (Gal-3), a protein that modulates inflammation and clearance of glucose adducts. We used Lean and Diet-induced Obese (DIO) WT and Gal-3 KO mice to investigate the role of Gal-3 in modulation of adiposity, glucose metabolism and inflammation. Deficiency of Gal-3 lead to age-dependent development of excess adiposity and systemic inflammation, as indicated by elevated production of acutephase proteins, number of circulating pro-inflammatory Ly6C high monocytes and development of neutrophilia, microcytic anemia and thrombocytosis in 20-week-old Lean and DIO male Gal-3 KO mice. This was associated with impaired fasting glucose, heightened response to a glucose tolerance test and reduced adipose tissue expression of adiponectin, Gal-12, ATGL and PPARc, in the presence of maintained insulin sensitivity and hepatic expression of gluconeogenic enzymes in 20week-old Gal-3 KO mice compared to their diet-matched WT controls. Expression of PGC-1a and FGF-21 in the liver of Lean Gal-3 KO mice was comparable to that observed in DIO animals. Impaired fasting glucose and altered responsiveness to a glucose load preceded development of excess adiposity and systemic inflammation, as demonstrated in 12-week-old Gal-3 KO mice. Finally, a role for the microflora in mediating the fasting hyperglycemia, but not the excessive response to a glucose load, of 12-week-old Gal-3 KO mice was demonstrated by administration of antibiotics. In conclusion, Gal-3 is an important modulator of glucose metabolism, adiposity and inflammation. Citation: Pang J, Rhodes DH, Pini M, Akasheh RT, Castellanos KJ et al. (2013) Increased Adiposity, Dysregulated Glucose Metabolism and Systemic Inflammation in Galectin-3 KO Mice. PLoS ONE 8(2): e57915.
Production of Annexin A1 (ANXA1), a protein that mediates the anti-inflammatory action of glucoco... more Production of Annexin A1 (ANXA1), a protein that mediates the anti-inflammatory action of glucocorticoids, is altered in obesity, but its role in modulation of adiposity has not yet been investigated. The objective of this study was to investigate modulation of ANXA1 in adipose tissue in murine models of obesity and to study the involvement of ANXA1 in diet-induced obesity in mice. Significant induction of ANXA1 mRNA was observed in adipose tissue of both C57BL6 and Balb/c mice with high fat diet (HFD)-induced obesity versus mice on chow diet. Upregulation of ANXA1 mRNA was independent of leptin or IL-6, as demonstrated by use of leptin-deficient ob/ob mice and IL-6 KO mice. Compared to WT mice, female Balb/c ANXA1 KO mice on HFD had increased adiposity, as indicated by significantly elevated body weight, fat mass, leptin levels, and adipocyte size. Whereas Balb/c WT mice upregulated expression of enzymes involved in the lipolytic pathway in response to HFD, this response was absent in ANXA1 KO mice. A significant increase in fasting glucose and insulin levels as well as development of insulin resistance was observed in ANXA1 KO mice on HFD compared to WT mice. Elevated plasma corticosterone levels and blunted downregulation of 11-beta hydroxysteroid dehydrogenase type 1 in adipose tissue was observed in ANXA1 KO mice compared to diet-matched WT mice. However, no differences between WT and KO mice on either chow or HFD were observed in expression of markers of adipose tissue inflammation. These data indicate that ANXA1 is an important modulator of adiposity in mice, with female ANXA1 KO mice on Balb/c background being more susceptible to weight gain and diet-induced insulin resistance compared to WT mice, without significant changes in inflammation.
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Papers by Jingbo Pang