PPARγ-Independent Increase in Glucose Uptake and Adiponectin Abundance in Fat Cells

Abstract

Although thiazolidinediones (TZD) effectively improve hyperglycemia and increase adiponectin, a proinsulin-sensitizing adipokine, they also increase adipogenesis via peroxisome proliferator-activated receptor (PPAR)γ induction, which may be undesirable. Recent safety concerns about some TZD have prompted the search for next generation agents that can enhance glycemic control and adiponectin independent of PPARγ or adipogenesis. Reminiscent of TZD action, a human adenovirus, adenovirus 36 (Ad36), up-regulates PPARγ, induces adipogenesis, and improves systemic glycemic control in vivo. We determined whether this effect of Ad36 requires PPARγ and/or adipogenesis. Glucose uptake and relevant cell signaling were determined in mock-infected or human adenoviruses Ad36 or Ad2-infected cell types under the following conditions: 1) undifferentiated human-adipose-tissue-derived stem cells (hASC), 2) hASC differentiated as adipocytes, 3) hASC in presence or absence of a PPARγ inhibitor, 4) NIH/3T3 that have impaired PPARγ expression, and 5) PPARγ-knockout mouse embryonic fibroblasts. Mouse embryonic fibroblasts with intact PPARγ served as a positive control. Additionally, to determine natural Ad36 infection, human sera were screened for Ad36 antibodies. In undifferentiated or differentiated hASC, or despite the inhibition, down-regulation, or the absence of PPARγ, Ad36 significantly enhanced glucose uptake and PPARγ, adiponectin, glucose transporter 4, and glucose transporter 1 protein abundance, compared with mock or Ad2-infected cells. This indicated that Ad36 up-regulates glucose uptake and adiponectin secretion independent of adipogenesis or without recruiting PPARγ. In humans, natural Ad36 infection predicted greater adiponectin levels, suggesting a human relevance of these effects. In conclusion, Ad36 provides a novel template to metabolically remodel human adipose tissue to enhance glycemic control without the concomitant increase in adiposity or PPARγ induction associated with TZD actions.

Glucagon-like peptide 1 regulates adipogenesis in 3T3-L1 preadipocytes

“…Ascofuranone, which has an anti-hyperlipidemia effect, can also increase the levels of PPAR-γ and adiponectin in 3T3-L1 preadipocyte cells (31). Previous studies have revealed that GLP-1 increases insulin sensitivity by upregulating Glut-4, thus reducing macrophage infiltration, inhibiting inflammatory pathways and reducing fat mass in adipocytes (29,30). Our results suggest an alternative mechanism whereby GLP-1 increases insulin sensitivity.…”

“…It has also been reported that an increase in the number of small subcutaneous adipocytes promotes lipid metabolism and insulin sensitivity (9,(29)(30)(31). The PPAR-γ agonist TZD has been shown to stimulate preadipocyte differentiation, to increase the number of small subcutaneous adipose cells, to improve insulin sensitivity and to prevent excess lipid accumulation through the upregulation of the expression of Glu-4 and adiponectin (29,30).…”

“…The PPAR-γ agonist TZD has been shown to stimulate preadipocyte differentiation, to increase the number of small subcutaneous adipose cells, to improve insulin sensitivity and to prevent excess lipid accumulation through the upregulation of the expression of Glu-4 and adiponectin (29,30). Ascofuranone, which has an anti-hyperlipidemia effect, can also increase the levels of PPAR-γ and adiponectin in 3T3-L1 preadipocyte cells (31).…”

Longitudinal investigation of adenovirus 36 seropositivity and human obesity: the Cardiovascular Risk in Young Finns Study

“…The Adv36 DNA in differentiated cells 95 expresses transcription factors and induce enzymes that may contribute to the development of 96 obesity by a variety of mechanisms. For example, Adv36 infection is associated with 97 increased differentiation of adipocytes and pre-adipocytes in vitro 8 , along with evidence of 98 increased glucose uptake and de novo lipogenesis 12 , and with recruitment of adipocytes from 99 adult stem cells within adipose tissue 13,14 . Therefore, Adv36 appears to induce both 100 hypertrophy and hyperplasia of fat cells.…”

Correlation between PPARg2 gene Pro12Ala polymorphism and cerebral infarction in an Inner Mongolian Han Chinese population

“…Atherosclerosis, the inflammatory response, and impaired vascular endothelial function play an important role in the development of cerebral infarction (Pucci et al, 2011;Soskić et al, 2011). The fact that PPARγ mediates effects on atherosclerosis, insulin resistance, inflammation, and lipoprotein metabolism may be relevant to this disease (Gallardo-Soler et al, 2008;Dubuisson et al, 2011).…”