Lactate production is a prioritized feature of adipocyte metabolism

Krycer, James R.; Quek, Lake Ee; Francis, Dorthe; Fazakerley, Daniel J.; Elkington, Sarah D.; Díaz-Vegas, Alexis; Cooke, Kristen C.; Weiss, Fiona C.; Duan, Xiaowen; Kurdyukov, Sergey; Zhou, Ping; Tambar, Uttam K.; Hirayama, Akiyoshi; Ikeda, Satsuki; Kamei, Yushi; Soga, Tomoyoshi; Cooney, Gregory J.; James, David E.

doi:10.1074/jbc.ra119.011178

Cited by 51 publications

(88 citation statements)

References 71 publications

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“…Consequently, we examined the sensitivity of mitoROS to glucose uptake. As observed previously (21), glucose uptake increased with insulin and higher media glucose concentrations ( Fig S2C). PRDX3 dimerisation also increased under these conditions ( Fig 2F,G), particularly when physiological glucose concentrations (and the K m of GLUT4 (22)) were reached.…”

Section: Glucose Is Required For Insulin-dependent Mitoros Productionsupporting

confidence: 87%

“…Finally, glucose only impacted respiration under maximal respiratory demand, whereby both insulin and glucose were required to increase further respiration in the presence of an uncoupler (Fig 1). Indeed, treatment with a mitochondrial uncoupler increased glucose oxidation substantially higher than insulin alone (21). Collectively, this suggests that insulin stimulates energy demand in adipocytes, but this increased demand is not enough to require substrate supply from exogenous glucose.…”

Section: Discussionmentioning

confidence: 97%

“…Since respiratory complexes also participate in mitoROS production (e.g., (19,20)), this raised the possibility that insulin treatment may similarly increase mitoROS levels independently of insulin-stimulated glucose metabolism. To maximise glucose oxidation, we utilised dichloroacetate (DCA), which causes the dephosphorylation of pyruvate dehydrogenase to promote the activity of this enzyme (21). Interestingly, although DCA rapidly decreased media acidification (Fig 2A), DCA treatment had little effect on global respiration (Fig 2B), even under maximal bioenergetic demand (BAM15).…”

Section: Glucose Is Required For Insulin-dependent Mitoros Productionmentioning

confidence: 99%

“…Lactate content was assayed enzymatically using the hydrazine sink method, as described previously (21,39).…”

Section: Quantification Of Lactate Contentmentioning

confidence: 99%

“…Glucose uptake was determined by measuring the disappearance of media glucose, as described previously (21,24). This differs from the measurement of glucose transport, which is described below.…”

Section: Quantification Of Glucose Uptakementioning

confidence: 99%

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Mitochondrial oxidants, but not respiration, are sensitive to glucose in adipocytes

Krycer

Elkington

Díaz-Vegas

et al. 2020

Journal of Biological Chemistry

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Insulin action in adipose tissue is crucial for whole-body glucose homeostasis, with insulin resistance being a major risk factor for metabolic diseases such as type 2 diabetes. Recent studies have proposed mitochondrial oxidants as a unifying driver of adipose insulin resistance, serving as a signal of nutrient excess. However, neither the substrates for nor sites of oxidant production are known. Since insulin stimulates glucose utilisation, we hypothesised that glucose oxidation would fuel respiration, in turn generating mitochondrial oxidants. This would impair insulin action, limiting further glucose uptake in a negative feedback loop of 'glucose-dependent' insulin resistance. Using primary rat adipocytes and cultured 3T3-L1 adipocytes, we observed that insulin increased respiration, but notably this occurred independently of glucose supply. In contrast, glucose was required for insulin to increase mitochondrial oxidants. Despite rising to similar levels as when treated with other agents that cause insulin resistance, glucosedependent mitochondrial oxidants failed to cause insulin resistance. Subsequent studies revealed a temporal relationship whereby mitochondrial oxidants needed to increase before the insulin stimulus to induce insulin resistance. Together, these data reveal that a) adipocyte respiration is principally fuelled from non-glucose sources, b) there is a disconnect between respiration and oxidative stress, whereby mitochondrial oxidant levels do not rise with increased respiration unless glucose is present, and c) mitochondrial oxidative stress must precede the insulin stimulus to cause insulin resistance, explaining why short-term insulin-dependent glucose utilisation does not promote insulin resistance. These data provide additional clues to mechanistically link nutrient excess to adipose insulin resistance. Adipose tissue is a key nutrient sensor in mammals (1). Being highly sensitive to insulin, adipocytes respond to nutrient replete conditions by increasing energy intake and storage as lipid. Conversely, under nutrient excess, adipocytes become insulin resistant, leading to increased lipid utilisation and reduced glucose intake. Indeed, impaired glucose uptake into adipose tissue is one of the earliest defects observed in whole-body insulin resistance, in both rodents and humans (e.g., (2

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Section: Glucose Is Required For Insulin-dependent Mitoros Productionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 97%