Knockdown of ANT2 reduces adipocyte hypoxia and improves insulin resistance in obesity

Seo, Jong Bae; Riopel, Matthew; Cabrales, Pedro; Huh, Jin Young; Bandyopadhyay, Gautam; Andreyev, Aleksander; Murphy, Anne N.; Beeman, Scott C.; Smith, Gordon I.; Klein, Samuel; Lee, Yun Sok; Olefsky, Jerrold M.

doi:10.1038/s42255-018-0003-x

Cited by 74 publications

(73 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The delivery of oxygen to adipose tissue is likely lower in people with obesity than in people who are lean because of decreased systemic arterial oxygen content associated with pulmonary dysfunction (120,121), decreased adipose tissue capillary density and perfusion (122)(123)(124)(125), an increased number of interstitial immune cells (126), and possibly greater oxygen diffusion distance due to hypertrophied adipocytes and increased ECM content (127). However, the adequacy of adipose tissue oxygenation in people with obesity is not clear, because interstitial adipose tissue oxygen partial pressure (pO 2 ), not intracellular pO 2 , is measured and because of conflicting data from different studies depending on the method used (120,(123)(124)(125)(128)(129)(130). Studies that used a Clark-type electrode or a fiber optic system to assess interstitial SAAT pO 2 in situ found that pO 2 was lower in people who are obese than in those who are lean (123,124,128,129).…”

Section: Review Series: Mechanisms Underlying the Metabolic Syndromementioning

confidence: 99%

“…However, the adequacy of adipose tissue oxygenation in people with obesity is not clear, because interstitial adipose tissue oxygen partial pressure (pO 2 ), not intracellular pO 2 , is measured and because of conflicting data from different studies depending on the method used (120,(123)(124)(125)(128)(129)(130). Studies that used a Clark-type electrode or a fiber optic system to assess interstitial SAAT pO 2 in situ found that pO 2 was lower in people who are obese than in those who are lean (123,124,128,129). In contrast, studies that used an optochemical sensor to measure pO 2 in SAAT interstitial fluid extracted by microdialysis ex vivo found that pO 2 was higher in people with obesity than in those who were lean despite decreased adipose tissue blood flow in people with obesity, suggesting decreased adipose tissue oxygen consumption in the obese group (125,130).…”

Section: Review Series: Mechanisms Underlying the Metabolic Syndromementioning

confidence: 99%

See 1 more Smart Citation

Metabolically healthy obesity: facts and fantasies

Smith¹,

Mittendorfer²,

Klein³

2019

Journal of Clinical Investigation

Self Cite

379

371

View full text Add to dashboard Cite

Section: Review Series: Mechanisms Underlying the Metabolic Syndromementioning

confidence: 99%

Section: Review Series: Mechanisms Underlying the Metabolic Syndromementioning

confidence: 99%

Metabolically healthy obesity: facts and fantasies

Smith¹,

Mittendorfer²,

Klein³

2019

Journal of Clinical Investigation

Self Cite

379

371

View full text Add to dashboard Cite

“…In rodent models of obesity, rapid weight gain is accompanied with increased expression of genes related to hypoxia, lower partial oxygen pressure, and an increase in hypoxic areas in adipose tissue . Also, decreasing adipocyte oxygen consumption and hypoxia by Ant2 knockdown in obese mice has led to decreased inflammation and improved glucose tolerance . In human obesity, oxygen pressure in adipose tissue has been reported as reduced in individuals with obesity versus lean individuals .…”

Section: Mitochondrial Metabolism In White At In Health and In Obesitymentioning

confidence: 99%

White adipose tissue mitochondrial metabolism in health and in obesity

et al. 2019

View full text Add to dashboard Cite

White adipose tissue is one of the largest organs of the body. It plays a key role in whole-body energy status and metabolism; it not only stores excess energy but also secretes various hormones and metabolites to regulate body energy balance. Healthy adipose tissue capable of expanding is needed for metabolic well-being and to prevent accumulation of triglycerides to other organs. Mitochondria govern several important functions in the adipose tissue. We review the derangements of mitochondrial function in white adipose tissue in the obese state. Downregulation of mitochondrial function or biogenesis in the white adipose tissue is a central driver for obesity-associated metabolic diseases. Mitochondrial functions compromised in obesity include oxidative functions and renewal and enlargement of the adipose tissue through recruitment and differentiation of adipocyte progenitor cells. These changes adversely affect whole-body metabolic health. Dysfunction of the white adipose tissue mitochondria in obesity has long-term consequences for the metabolism of adipose tissue and the whole body. Understanding the pathways behind mitochondrial dysfunction may help reveal targets for pharmacological or nutritional interventions that enhance mitochondrial biogenesis or function in adipose tissue. KEYWORDS adipose tissue, mitochondria, obesity 1 | INTRODUCTION Obesity is a global and rapidly increasing problem, tripled since 1975 by WHO 2018 standards in developed countries. Obesity is also extremely difficult to treat. A key defining feature of obesity is an adipose tissue dysfunction, which is considered to be a major contributor to the development of obesity-related metabolic problems, 1,2 such as metabolic syndrome, insulin resistance, hypertension, dyslipidaemia, and fatty liver. The underlying pathological mechanisms that impair adipose tissue function in obesity are incompletely understood, but in the light of recent scientific advances, it may be connected to insufficient storage capacity or impaired function of mitochondria, or both. Mitochondria are the energy centres of adipocytes and are involved in many of their key metabolic functions including ATP production, fatty acid synthesis and oxidation, and the triglyceride balance of the cell. Although adipose tissue was long considered as an inert reservoir of fat with low abundance of mitochondria, adipose tissue and its active mitochondria have recently emerged as one of the central regulators influencing whole-body metabolism. 1,3,4 Impairments in adipocyte mitochondrial function are associated with metabolic diseases and the development of obesity-related disorders. 3-6Better understanding on the dysfunction of adipose tissue mitochondria may yield insights on how the metabolic complications of obesity could be reversed. In this review, we concentrate on the metabolic processes in white adipose tissue that are regulated by mitochondria /journal/obr 1 of 23 23 of like bariatric surgery that seem to preserve a favourable metabolic profile in adipose tissue should be ...

show abstract

“…ANT2 gene knockout improves insulin sensitivity in two studies of fat and liver in mice [33; 34]. The exact mechanism remains to be investigated for the enhanced insulin action although a reduction in inflammation was proposed [33]. Mitophagy removes the senescent and damaged mitochondria through self-digestion [35], a process triggered by multiple factors including energy deficiency [36].…”

Section: Discussionmentioning

confidence: 99%

IF1 connects obesity and insulin resistance through mitochondrial reprogramming in association with ANT2

Wang

Guan

Zhang

et al. 2020

Preprint

View full text Add to dashboard Cite

IF1 (ATPIF1) is a nuclear DNA-encoded protein with an activity in the inhibition of catalytic activity of F1Fo-ATP synthase (ATPase), an enzyme for ATP synthesis in mitochondria. A role of IF1 remains unknown in the metabolic disorder in obesity. In this study, IF1 was examined in the diet-induced obese (DIO) mice and a decrease in IF1 protein was observed in several tissues including the skeletal muscle, liver and intestine in the absence of mRNA alteration. Significance of the reduction was investigated in the IF1-KO mice, in which insulin sensitivity was improved in the absence of body weight alteration on Chow diet. On a high fat diet (HFD), the IF1-KO mice gain more body weight as a result of enhanced fat tissue growth. The energy expenditure and locomotion activity were decreased in the KO mice without an alteration in food intake. The increase in insulin sensitivity remained in the obese KO mice. The colon tissue exhibited a resistance to the HFD-induced atrophy with less cell apoptosis and more secretion of GLP-1. Mitochondria exhibited an enhanced ATP production and maximal oxygen consumption without an alteration in the respiratory chain proteins. However, the ATP level was reduced in the fasting condition in the muscle as well as the liver. Mitophagy was enhanced with elevated accumulation of PINK1 and Parkin proteins in the mitochondria. The protein abundance of ADP/ATP translocase 2 (ANT2) was decreased in the inner membrane of mitochondria to account for the reduced apoptosis and enhanced mitophagy. The data suggest that the IF1 reduction in obesity leads to reprogramming of mitochondrial metabolism in a compensatory response to maintain the insulin sensitivity through down-regulation of ANT2 protein.

show abstract

Knockdown of ANT2 reduces adipocyte hypoxia and improves insulin resistance in obesity

Cited by 74 publications

References 51 publications

Metabolically healthy obesity: facts and fantasies

Metabolically healthy obesity: facts and fantasies

White adipose tissue mitochondrial metabolism in health and in obesity

IF1 connects obesity and insulin resistance through mitochondrial reprogramming in association with ANT2

Contact Info

Product

Resources

About