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 ...

Obesity, a chronic state of energy overload, is characterized by adipose tissue dysfunction that is considered to be the major driver for obesity associated metabolic complications. The reasons for adipose tissue dysfunction are incompletely understood, but one potential contributing factor is adipose tissue mitochondrial dysfunction. Derangements of adipose tissue mitochondrial biogenesis and pathways associate with obesity and metabolic diseases. Mitochondria are central organelles in energy metabolism through their role in energy derivation through catabolic oxidative reactions. The mitochondrial processes are dependent on the proper NAD+/NADH redox balance and NAD+ is essential for reactions catalyzed by the key regulators of mitochondrial metabolism, sirtuins (SIRTs) and poly(ADP-ribose) polymerases (PARPs). Notably, obesity is associated with disturbed adipose tissue NAD+ homeostasis and the balance of SIRT and PARP activities. In this review we aim to summarize existing literature on the maintenance of intracellular NAD+ pools and the function of SIRTs and PARPs in adipose tissue during normal and obese conditions, with the purpose of comprehending their potential role in mitochondrial derangements and obesity associated metabolic complications. Understanding the molecular mechanisms that are the root cause of the adipose tissue mitochondrial derangements is crucial for developing new effective strategies to reverse obesity associated metabolic complications.

Mitochondrial DNA (mtDNA) sequence variants segregate in mutation and tissue-specific manners, but the mechanisms remain unknown. The segregation pattern of pathogenic mtDNA mutations is a major determinant of the onset and severity of disease. Using a heteroplasmic mouse model, we demonstrate that Gimap3, an outer mitochondrial membrane GTPase, is a critical regulator of this process in leukocytes. Gimap3 is important for T cell development and survival, suggesting that leukocyte survival may be a key factor in the genetic regulation of mtDNA sequence variants and in modulating human mitochondrial diseases.

Highlights d Multiomics analyses of adipose tissue and skeletal muscle in BMI-discordant twins d Excess body weight downregulates mitochondrial pathways in both tissues d Excess body weight upregulates proinflammatory pathways in both tissues d Adipose tissue alterations are associated with metabolic health in acquired obesity

Context Mitochondria are essential for cellular energy homeostasis, yet their role in subcutaneous adipose tissue (SAT) during different types of weight-loss interventions remains unknown. Objective Investigate how SAT mitochondria change following diet-induced and bariatric surgery-induced weight-loss interventions in four independent weight-loss studies. Design/Setting The DiOGenes study is a European multicenter dietary intervention with an 8-week low caloric diet (LCD; 800 kcal/d; n=261) and 6-month weight maintenance (n=121) period. The Kuopio Obesity Surgery study (KOBS) is a Roux-en-Y gastric bypass (RYGB) surgery study (n=172) with a 1-year follow-up. We associated weight-loss percentage with global and 2210 mitochondria-related RNA transcripts in linear regression analysis adjusted for age and sex. We repeated these analyses in two studies. The Finnish CRYO study has a 6-week LCD (800–1000 kcal/d; n=19) and a 10.5-month follow-up. The Swedish DEOSH study is a RYGB surgery study with a 2-year (n=49) and 5-year (n=37) follow-up. Results Diet-induced weight loss led to a significant transcriptional downregulation of oxidative phosphorylation (DiOGenes; Ingenuity Pathway Analyses (IPA) z-scores: -8.7 following LCD, -4.4 following weight maintenance; CRYO: IPA z-score: -5.6, all p<0.001), while upregulation followed surgery-induced weight loss (KOBS: IPA z-score: 1.8, p<0.001; in DEOSH: IPA z-scores: 4.0 following 2 years, 0.0 following 5 years). We confirmed an upregulated oxidative phosphorylation at the proteomics level following surgery (IPA z-score: 3.2, p<0.001). Conclusions Differentially regulated SAT mitochondria-related gene expressions suggest qualitative alterations between weight-loss interventions, providing insights into the potential molecular mechanistic targets for weight-loss success.