Ascent to altitude as a weight loss method: the good and bad of hypoxia inducible factor activation

Abstract

Objective: Given the epidemic of obesity worldwide there is a need for more novel and effective weight loss methods. Altitude is well known to be associated with weight loss and has actually been used as a method of weight reduction in obese subjects. This review demonstrates the critical role of hypoxia inducible factor (HIF) in bringing about reductions in appetite and increases in energy expenditure characteristic of hypobaric hypoxia

Design and methods: A MEDLINE search of English language articles through February 2013 identified publications associating altitude or hypobaric hypoxia with key words to include HIF, weight loss, appetite, basal metabolic rate, leptin, cellular energetics, and obesity. The data from these articles were synthesized to formulate a unique and novel mechanism by which HIF activation leads to alterations in appetite, basal metabolic rate, and reductions in body adiposity.

Results: A synthesis of previously published literature revealed mechanisms by which altitude induces activation of HIF, thereby suggesting this transcription factor regulates changes in cellular metabolism/energetics, activation of the central nervous system, as well as peripheral pathways leading to reductions in food intake and increases in energy expenditure.

Conclusions: Here a unifying hypothesis is present suggesting that activation of HIF under conditions of altitude potentially leads to metabolic benefits that are dose dependent, gender and genetic specific, and results in adverse effects if the exposure is extreme.

Copyright © 2013 The Obesity Society.

Figures

Figure 1

Under condition of limited oxygen supply upregulation of hypoxia inducible factor leads to a shift in cell metabolism favoring glycolysis so as to limit generation of potentially harmful reactive oxygen species via oxidative phosphorylation in the mitochondria. A critical step in this shift is HIF-mediated activation of pyruvate dehydrogenase kinase-1 (PDK-1). This enzyme inactivates pyruvate kinase which is the mitochondrial enzyme responsible for converting pyruvate to acetyl-CoA. In combination with activation of lactate dehydrogenase A (LDHA) which converts pyruvate to lactate, there is less delivery of acetyl-CoA into the Krebs cycle and therefore a reduction of flavin adenine dinucleotide (FADH2) and nicotinamide adenine dinucleotide (NADH) delivered to the electron transport chain. HIF up regulates the expression of GLUT1 and GLUT3 on the cell membrane so as to facilitate glucose entry into the cell. HIF also up regulates monocarboxylate transporter 4 which is a proton-lactate symporter. This transporter creates an avenue for lactate exit from the cell. The cotransport of the proton contributes to the maintenance of intracellular pH. Cell pH is also defended by HIF-induced expression of carbonic anhydrase-9 and increased expression of the Na+/H+ antiporter, NHE1.

Figure 2

An increase in Cori cycle activity under conditions of hypoxia can supply the necessary substrate to fuel the greater dependency on blood glucose brought about by increased HIF activity. Under conditions of hypoxia both hepatic lactate uptake and glucose production are increased. HIF up-regulates the gene expression of phosphoenolpyruvate carboxykinase which is the rate limiting enzyme for gluconeogenesis. This change in metabolism is energy inefficient since only 2 ATP’s are formed for each mol of glucose metabolized and 6 ATP’s are consumed for every 2 molecules of lactate converted to glucose. This energy wasting may play a role in the increase in basal metabolic rate which occurs at altitude. This energy inefficiency may also be detrimental to exercise performance at altitude do to the shift away from mitochondrial respiration where up to 34 ATP’s are formed for each mol of glucose metabolized.

Figure 3

Circulating leptin is transported across the blood brain barrier where it binds to key hypothalamic neuronal sites such as in the arcuate nucleus and specifically on the proopiomelanocortin (POMC) neuron. This interaction leads to release of the POMC-derived neuropeptide, α-melanocyte stimulating hormone (α-MSH) which in turns binds to melanocortin 4 receptors in the paraventricular nucleus. The POMC/ MC4-R system mediates leptin signaling to induce anorectic effects. MC4R activation also increases peripheral sympathetic nerve activity, probably by both direct and indirect signaling processes, leading to increased expression and activity of mitochondrial uncoupling protein 1 (UCP-1) in brown adipose tissue. This protein uncouples oxidative phosphorylation causing an increase in thermogenesis and increased energy expenditure. Sympathetic nerve activity stimulated by leptin is subject to negative feedback as catecholamines inhibit leptin gene expression in fat through β-adrenergic receptors.