Abstract
We live and to do so we must breathe and eat, so are we a combination of what we eat and breathe? Here, we will consider this question, and the role in this respect of the AMP-activated protein kinase (AMPK). Emerging evidence suggests that AMPK facilitates central and peripheral reflexes that coordinate breathing and oxygen supply, and contributes to the central regulation of feeding and food choice. We propose, therefore, that oxygen supply to the body is aligned with not only the quantity we eat, but also nutrient-based diet selection, and that the cell-specific expression pattern of AMPK subunit isoforms is critical to appropriate system alignment in this respect. Currently available information on how oxygen supply may be aligned with feeding and food choice, or vice versa, through our motivation to breathe and select particular nutrients is sparse, fragmented and lacks any integrated understanding. By addressing this, we aim to provide the foundations for a clinical perspective that reveals untapped potential, by highlighting how aberrant cell-specific changes in the expression of AMPK subunit isoforms could give rise, in part, to known associations between metabolic disease, such as obesity and type 2 diabetes, sleep-disordered breathing, pulmonary hypertension and acute respiratory distress syndrome.
Highlights
It is evident that we must breathe without serious interruption from birth to death, and we do so with such ease that it almost goes unnoticed, whether we cough, sneeze, snort or, from our partners’ perspective, snore
Breathing is coordinated by a sophisticated motor program, which develops in utero in order to coordinate lung ventilation after birth, and responds appropriately to changes in oxygen demand during such activities as exercise, sleep or ascent to altitude
Emerging evidence strongly suggests that the adenosine monophosphate (AMP)-activated protein kinase (AMPK) might facilitate both HVR and HPV [10]. This hypothesis [11,12] was built on prior observations that mitochondria of oxygen-sensing cells were exquisitely sensitive to hypoxia, and the proposal that this was due to the selective expression in these cells of a form of cytochrome C oxidase (COX) that was uniquely sensitive to changing PO2 within the physiological range [13,14]
Summary
It is evident that we must breathe without serious interruption from birth to death, and we do so with such ease that it almost goes unnoticed, whether we cough, sneeze, snort or, from our partners’ perspective, snore. Emerging evidence strongly suggests that the AMP-activated protein kinase (AMPK) might facilitate both HVR and HPV [10] This hypothesis [11,12] was built on prior observations that mitochondria of oxygen-sensing cells were exquisitely sensitive to hypoxia, and the proposal that this was due to the selective expression in these cells of a form of cytochrome C oxidase (COX) that was uniquely sensitive to changing PO2 within the physiological range [13,14]. Carotid body type I cell responsiveness to acute hypoxia and acute HVR are abolished in mice by conditional deletion of Cox4I2 in tyrosine hydroxylase expressing catecholaminergic cells [27], while HPV is occluded in isolated, ventilated and perfused lungs from Cox4I2 knockout mice [28] These atypical nuclear encoded subunits represent a further distinguishing feature of oxygen-sensing cells, but, at least in the case of COX4I2, appear to be critically important for hypoxia-response coupling within the physiological range of PO2. It appears that, during evolution, the role of AMPK in regulating metabolic homeostasis has been extended through natural selection to support system-level control of substrate supply (e.g., of oxygen, glucose and fatty acids) in order to maintain energy (ATP) homeostasis across the whole body [11]
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