Adiponectin downregulates its own production and the expression of its AdipoR2 receptor in transgenic mice.
Adiponectin (ApN) is an adipokine whose expression and plasma levels are inversely related to obesity and insulin-resistant states. The in vivo effects of a chronic expression of exogenous ApN restricted to adipose tissue are unclear. Moreover, the regulatory effects of ApN on its own expression and on that of its receptors are still unknown. In this study, we generated transgenic (Tg) mice with moderate expression of exogenous ApN targeted to adipose tissue (native full-length ApN being placed under control of the adipocyte promoter aP2). After a transient overexpression of ApN in young pups, we intriguingly observed a reduction of ApN mRNA levels and protein content in fat depots, together with a decrease of circulating ApN in adult mice. As a result, the phenotype of these adult mice included glucose intolerance, insulin resistance, and increased adiposity. Reduced expression of ApN in fat tissue was associated with diminished expression of uncoupling protein 2 involved in energy dissipation, and higher expression of fatty acid synthase, a key enzyme of lipogenesis, and of TNFalpha implicated in insulin resistance. Concomitantly, the expression of the ApN receptor AdipoR2 that mediates action of full-length ApN was downregulated, while that of AdipoR1 was unaffected. In agreement with the in vivo studies, recombinant ApN added to the culture medium of 3T3-F442A adipocytes caused a decrease in AdipoR2 and ApN mRNA levels. This treatment did not affect the expression of AdipoR1. Eventually, we demonstrated a contrario that AdipoR2 (but not R1) was specifically upregulated in fat of ApN(-/-) mice. Our in vivo and in vitro data provide evidence for a novel regulatory feedback loop by which ApN downregulates its own production and the expression of its AdipoR2 receptor.
Bauche
Isabelle B
IB
Endocrinology and Metabolism Unit, University of Louvain, Faculty of Medicine, Brussels, Belgium.
Ait El Mkadem
Samira
S
Rezsohazy
René
R
Funahashi
Tohru
T
Maeda
Norikazu
N
Miranda
Lisa Miranda
LM
Brichard
Sonia M
SM
D016475:3T3 Cells; D055372:AMP-Activated Protein Kinases; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D052242:Adiponectin / Q000097:blood / Q000235:genetics* / Q000494:pharmacology; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D015152:Blotting, Northern; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000493:pharmacokinetics; D005951:Glucose Tolerance Test; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009097:Multienzyme Complexes / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054419:Receptors, Adiponectin; D011956:Receptors, Cell Surface / Q000235:genetics*; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
D052242:Adiponectin; D001786:Blood Glucose; D009097:Multienzyme Complexes; D012333:RNA, Messenger; D054419:Receptors, Adiponectin; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; C475421:adiponectin receptor 2, mouse; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose