Mitochondrial oxidants, but not respiration, are sensitive to glucose in adipocytes.
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. Because insulin stimulates glucose utilization, we hypothesized 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, glucose-dependent 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 fueled from nonglucose 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 utilization does not promote insulin resistance. These data provide additional clues to mechanistically link nutrient excess to adipose insulin resistance.
Pubmed ID: 31744882 RIS Download
Research resources used in this publication
Additional research tools detected in this publication
None foundAntibodies used in this publication
- Peroxiredoxin 2 antibody [EPR5154] (RRID:AB_10862524)
- PRDX3 Polyclonal Antibody (RRID:AB_2252752)
- Anti-phospho-PDHE1-A type I (Ser293) (RRID:AB_11205754)
- pan 14-3-3 (K-19) (RRID:AB_2273154)
- PDH-E1alpha (H-131) (RRID:AB_10990923)
- Phospho-AS160 (Thr642) Antibody (RRID:AB_10545274)
- Akt (pan) (11E7) Rabbit mAb (RRID:AB_2225340)
- Phospho-Akt (Thr308) Antibody (RRID:AB_329828)
- Phospho-Akt (Ser473) (587F11) Mouse mAb (RRID:AB_331158)
Associated grants
- Agency: Medical Research Council, United Kingdom
Id: MR/S007091/1
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This is a list of tools and resources that we have found mentioned in this publication.
Peroxiredoxin 2 antibody [EPR5154] (antibody)
RRID:AB_10862524
This monoclonal targets Peroxiredoxin 2 antibody [EPR5154]
View all literature mentionsPRDX3 Polyclonal Antibody (antibody)
RRID:AB_2252752
This unknown targets PRDX3
View all literature mentionsAnti-phospho-PDHE1-A type I (Ser293) (antibody)
RRID:AB_11205754
This polyclonal targets phospho-PDHE1-A type I (Ser293)
View all literature mentionspan 14-3-3 (K-19) (antibody)
RRID:AB_2273154
This polyclonal targets unknown
View all literature mentionsPDH-E1alpha (H-131) (antibody)
RRID:AB_10990923
This monoclonal targets PDH-E1alpha (H-131)
View all literature mentionsPhospho-AS160 (Thr642) Antibody (antibody)
RRID:AB_10545274
This polyclonal targets Phospho-AS160 (Thr642)
View all literature mentionsAkt (pan) (11E7) Rabbit mAb (antibody)
RRID:AB_2225340
This monoclonal targets Akt2
View all literature mentionsPhospho-Akt (Thr308) Antibody (antibody)
RRID:AB_329828
This polyclonal targets
View all literature mentionsPhospho-Akt (Ser473) (587F11) Mouse mAb (antibody)
RRID:AB_331158
This monoclonal targets Phospho-Akt (Ser473) (587F11) Mouse mAb
View all literature mentions
