New insulin sensitisers produce differentiation of brown-like adipose cells from a subcutaneous fat depot and increase secretion of adiponectin
Tuesday, Sep 13, 2011, 11:15 AM -11:30 AM
, S.L. Cole, D.D. Holewa, A.S. Brightwell-Conrad, P.K. Harris, J.R. Colca, R.F. Kletzien;
Metabolic Solutions Development Co., Kalamazoo, MI, USA.
31 Adipose tissue biology and adipocytokines
Background and aims
Subcutaneous adipose depots have been suggested to play an important role in promoting insulin sensitivity in rodents and man. The subcutaneous adipose depots are also a major source of adiponectin, an adipokine with salutary hormone sensitizing effects on insulin target tissues. New insulin sensitizers that do not bind to or activate PPARγ at micromolar concentrations [PPARγ-sparing thiazolidinediones (PsTZDs)] have been used to evaluate the possible influence of the PsTZDs on subcutaneous adipose tissue.
Materials and methods:
Progenitor cells from axillary adipose depots were isolated from CD-1 mice and placed in tissue culture under defined conditions. Treatment of these cells with PsTZDs, including clinical candidate MSDC-0160, was used to examine PPARγ independent effects on both differentiation and the associated secretion of adiponectin.
Addition of the PsTZDs such as the clinical candidate MSDC-0160, elicited a time- and dose-dependent differentiation of the progenitor cells which exhibited a brown-like morphology with multilocular fat droplets and intense oil red O staining. Assessment of expression of the mitochondrial uncoupling protein (UCP1) revealed that 3 uM MSDC-0160 induced a greater than 2000-fold increase in UCP1 mRNA and a 20-fold increase in UCP1 protein within 7 days. Treatment with micromolar MSDC-0160 also produced a two-fold increase in mitochondrial biogenesis as measured by the mitochondrial marker, citrate synthase activity. These effects were not attenuated by the potent PPARγ antagonists, T0070907 and GW9662, confirming the PPAR-sparing nature of the drug action. Adiponectin expression in the cultures was also studied as a function of drug treatment. MSDC-0160 treatment produced a more than 15-fold increase in adiponectin mRNA within 6 days of drug treatment. Under these conditions, the secretion of adiponectin into the medium was also increased in a PPARγ-independent and time-dependent manner with maximal increases in secreted protein after 4 days of drug treatment in response to micromolar levels of compound.
In conclusion, we report that the PsTZDs elicit differentiation of progenitor cells from axillary adipose depots into brown-like adipose cells that express UCP1 message and protein in a process that includes increased mitochondrial biogenesis. Importantly, in contrast to the effects on brown adipose cells from the interscapular pad, the cells from axillary adipose depots also secreted adiponectin in response to the PsTZDs. Since activation of PPARγ is known to be responsible for dose limiting side effects of currently available insulin sensitizers, these results have important mechanistic implications for future therapies of type 2 diabetes and provide a framework for defining the key biochemical pathways involved in the action of PsTZDs, including production and secretion of adiponectin.
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