protein kinase (AMPK) and the histone/protein deacetylase SIRT1 are fuel-sensing molecules that have coexisted in cells throughout evolution. When a cell's energy state is diminished, AMPK activation restores energy balance by stimulating catabolic processes that generate ATP and downregulating anabolic processes that consume ATP but are not acutely needed for survival. SIRT1 in turn is best known historically for producing genetic changes that mediate the increase in longevity caused by calorie restriction. Although the two molecules have been studied intensively for many years, only recently has it become apparent that they have similar effects on diverse processes such as cellular fuel metabolism, inflammation, and mitochondrial function. In this review we will examine the evidence that these similarities occur because AMPK and SIRT1 both regulate each other and share many common target molecules. In addition, we will discuss the clinical relevance of these interactions and in particular the possibility that their dysregulation predisposes to disorders such as type 2 diabetes and atherosclerotic cardiovascular disease and is a target for their therapy.adenosine 5=-monophosphate-activated protein kinase; sirtuin 1; metabolic syndrome; mitochondrial function; insulin resistance; peroxisome proliferator-activated receptor-␥ coactivator-1␣; type 2 diabetes; atherosclerosis AMP-ACTIVATED PROTEIN KINASE (AMPK) is a fuel-sensing enzyme that is activated by decreases in a cell's energy state as reflected by an increased AMP/ATP ratio. When activated, it initiates metabolic and genetic events that restore ATP levels by stimulating processes that generate ATP (e.g., fatty acid oxidation) and inhibiting others that consume ATP but are not acutely required for survival (e.g., triglyceride and protein synthesis, cell proliferation) (40). In addition, AMPK sets in motion changes in mitochondrial biogenesis and function (37) that could more chronically increase the ability of a cell to generate ATP and diminish oxidative stress and other potentially adverse cellular events (78). The sirtuins are a family of evolutionarily conserved NAD ϩ -dependent histone/protein deacetylases that are also widely regarded as fuel-sensing molecules. They have many actions (see below) but are perhaps best known for their role in mediating the increase in longevity caused by caloric restriction in various species, including yeast, worms, and possibly mammals (21, 85). Seven sirtuins have been identified in mammalian cells. Of these the most studied and the focus of this review is silent information regulator T1 (SIRT1).AMPK and the sirtuins are present in all eukaryotic cells and probably have coexisted throughout evolution (7, 29). Although both molecules have been studied intensively, the similarities in their regulation and in their actions on such diverse processes as cellular metabolism, inflammation, and mitochondrial function have only recently become apparent. In this review we will examine the evidence that these similarities occur, ...

Activation of G-protein-coupled chemoattractant receptors triggers dissociation of Galpha and Gbetagamma subunits. These subunits induce intracellular responses that can be highly polarized when a cell experiences a gradient of chemoattractant. Exactly how a cell achieves this amplified signal polarization is still not well understood. Here, we quantitatively measure temporal and spatial changes of receptor occupancy, G-protein activation by FRET imaging, and PIP3 levels by monitoring the dynamics of PH(Crac)-GFP translocation in single living cells in response to different chemoattractant fields. Our results provided the first direct evidence that G-proteins are activated to different extents on the cell surface in response to asymmetrical stimulations. A stronger, uniformly applied stimulation triggers not only a stronger G-protein activation but also a faster adaptation of downstream responses. When naive cells (which have not experienced chemoattractant) were abruptly exposed to stable cAMP gradients, G-proteins were persistently activated throughout the entire cell surface, whereas the response of PH(Crac)-GFP translocation surprisingly consisted of two phases, an initial transient and asymmetrical translocation around the cell membrane, followed by a second phase producing a highly polarized distribution of PH(Crac)-GFP. We propose a revised model of gradient sensing, suggesting an important role for locally controlled components that inhibit PI3Kinase activity.

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