Regulation Of Adipocyte Function Research Articles

Opposing effects of tumour necrosis factor alpha and hyperosmolarity on Na+/myo-inositol co-transporter mRNA levels and myo-inositol accumulation by 3T3-L1 adipocytes.

Tumour necrosis factor alpha (TNF-alpha) regulates the transport of myo-inositol in 3T3-L1 adipocytes. Treating 3T3-L1 adipocytes with TNF-alpha decreases Na+/myo-inositol co-transporter (SMIT) mRNA levels and myo-inositol accumulation in a concentration-and time-dependent manner. TNF-alpha decreases the V'max for high-affinity myo-inositol transport with little change in the K'm. Studies with actinomycin D suggest that RNA synthesis is required for the TNF-alpha-induced effect on SMIT mRNA levels. In contrast with the effect of TNF-alpha, hyperosmolarity increases SMIT mRNA levels and myo-inositol accumulation in 3T3-L1 adipocytes. Hyperosmolarity increases SMIT gene expression as evidenced by the inhibition of hyperosmotic induction of SMIT mRNA levels by actinomycin D, and of myo-inositol accumulation by actinomycin D and cycloheximide. TNF-alpha and osmotic stress have previously been shown to activate similar signal transduction pathways in mammalian cells. In 3T3-L1 adipocytes, both TNF-alpha and hyperosmolarity increase mitogen-activated protein kinase kinase pathway activity; however, with the possible exception of c-Jun N-terminal kinase, this pathway does not seem to regulate SMIT mRNA levels or myo-inositol accumulation. TNF-alpha activates nuclear factor kappaB (NF-kappaB) in 3T3-L1 adipocytes but, unlike the effect of TNF-alpha on cultured endothelial cells, NF-kappaB does not seem to contribute to the regulation by TNF-alpha of SMIT gene expression in 3T3-L1 adipocytes. Therefore other signal transduction pathways must be considered in the regulation by TNF-alpha of SMIT mRNA levels and activity. Thus TNF-alpha and hyperosmolarity have opposing effects on SMIT mRNA levels and activity in 3T3-L1 adipocytes. Because myo-inositol in the form of phosphoinositides is an important component of membranes and signal transduction pathways, the regulation of myo-inositol metabolism by TNF-alpha might represent another mechanism by which TNF-alpha regulates adipocyte function.

Inhibition of insulin receptor signaling by TNF: Potential role in obesity and non-insulin-dependent diabetes mellitus

Adipocytes produce a variety of molecules that are capable of functioning in both a paracrine and autocrine fashion. Tumor necrosis factor (TNF) is one of the proteins produced by adipocytes that has been shown to regulate adipocyte function. Interestingly, adipocyte expression of TNF increases with increasing adipocyte mass and expression of TNF is increased in adipocytes isolated from several genetic models of rodent obesity and from obese humans. This finding has led to the idea that TNF produced by adipocytes functions as a local “adipostat” to limit fat accumulation. Increased production of TNF by adipocytes, however, may contribute to insulin resistance in obesity and in non-insulin-dependent diabetes mellitus (NIDDM). TNF has been shown to inhibit insulin-simulated tyrosine phosphorylation of both the insulin receptor (IR) and insulin receptor substrate (IRS)-I and to stimulate downregulation of the insulin-sensitive glucose transporter, GLUT4, in adipocytes. These findings raise the possibility that pharmacological inhibition of TNF may provide a novel therapeutic target to treat patients with NIDDM.

The Adipsin-ASP Pathway and Regulation of Adipocyte Function

The adipsin-ASP pathway provides a mechanism by which the adipocyte is able to regulate its rate of de novo triglyceride synthesis and reesterification. The adipocyte can synthesize and secrete the three proteins necessary for the formation of the effector molecule, acylation stimulating protein (ASP). ASP increases membrane transport of glucose and the activity of diacylglycerol acyltransferase and by virtue of both of these effects markedly increases the rate of triglyceride synthesis. Awareness of the pathway will allow, we believe, a new understanding of the regulation of triglyceride removal from plasma. Accordingly, the concept of microenvironmental metabolic regulation of triglyceride hydrolysis at the endothelial surface and triglyceride synthesis within the adipocyte will be presented. In addition, the pathogenetic sequence by which dysfunction of this pathway can lead to dyslipoproteinaemia will be reviewed. Emphasis, however, will be placed on the role this pathway may play in the pathogenesis of obesity and the adaptation to negative caloric balance in the obese.