NUTRITIONAL AND ENDOCRINE MODULATION OF INTRACELLULAR CALCIUM - IMPLICATIONS IN OBESITY, INSULIN-RESISTANCE AND HYPERTENSION

Regulation of intracellular Ca2+ ([Ca2+](i)) plays a key role in obesi ty, insulin resistance and hypertension, and [Ca2+](i) disorders may r epresent a fundamental factor linking these three conditions. We have shown insulin to be a direct vasodilator, attenuating voltage-gated Ca 2+ influx and stimulating Ca2+-ATPase transcription via a glucose-6-ph osphate response element. These result in a net decrease in [Ca2+](i) and thereby decrease vascular resistance, while these effects are blun ted in insulin resistance, leading to increased vascular resistance. C onsistent with this concept, pharmacological amplification of peripher al insulin sensitivity results in reduced arterial pressure. While ins ulin regulates [Ca2+](i), Ca2+ also regulates insulin signaling, as in creasing [Ca2+](i) impairs insulin signaling in some systems, possibly due to Ca2+ inhibition of insulin-regulated dephosphorylation. Finall y in recent studies of the mouse agouti gene, we have also demonstrate d increased [Ca2+](i) to play a key role in adipocyte lipogenesis, as follows. We have found dominant agouti mutants to exhibit increased [C a2+](i) in most tissues, leading to increased vascular reactivity and insulin resistance in vascular smooth muscle and skeletal muscle cells , respectively. Further, we have found recombinant agouti protein to d irectly increase [Ca2+](i) in a variety of cells, including murine and human adipocytes, and to stimulate both the expression and activity o f adipocyte fatty acid synthase and increase triglyceride accumulation in a Ca2+-dependent manner. These effects can be mimicked by stimulat ion of Ca2+ influx and blocked by Ca2+ channel inhibition, while treat ment of mice with a Ca2+ antagonist attenuates agouti-induced obesity. Since humans express agouti in adipose tissue, it may similarly exert paracrine effects on [Ca2+](i) and thereby stimulate de novo lipogene sis and promote obesity. Thus, Ca2+ signaling represents a target for therapeutic intervention in obesity as well as hypertension and insuli n resistance.