Best Practice & Research Clinical Endocrinology & Metabolism
7Mitochondria and endocrine function of adipose tissue
Introduction
With the growing pandemic of human obesity and its associated complications, interest in improving our understanding of the development, function and manipulation of adipose tissue has increased considerably.1 Particularly, the study of the adipocyte offers a great opportunity to explore the metabolic problems associated with the development of obesity.2 Excess adipose tissue is accompanied by an increase in the risk of developing insulin resistance and type 2 diabetes, dyslipidemia, hypertension, metabolic syndrome, coronary heart disease and stroke.3 The relationship between obesity and such complications is well-established at epidemiological level; however the mechanisms explaining this relationship are not fully defined.
Paradoxically, not only the excess of adipose tissue, but also the total or partial absence of fat is associated with insulin resistance and with an increase in the risk of cardiometabolic complications.4 Furthermore, many obese patients are metabolically healthy despite having fat accumulation, while other patients, who are only moderately obese, develop metabolic syndrome. This can be explained by the different capability that different individuals have to expand their adipose tissue. Thus, when the oxidative capacity and the storage capacity of adipocytes are compromised in an individual, the ectopic lipid accumulation would trigger lipotoxicity.5 This lipotoxic process is associated with a non-adipose based accumulation of triglycerides and other specific lipid metabolites such as ceramides and diacylglycerides, which alter the metabolism of these tissues, inhibit insulin action, bringing about deleterious effects.6
In mammals there are two general types of adipose tissue: white adipose tissue (WAT) and brown adipose tissue (BAT). WAT specializes in energy storage in the form of triglyceride (TG)-containing intracellular droplets as well as to secrete hormones that regulate energy balance. WAT was traditionally considered a metabolically active storage tissue for lipids. Nowadays, many studies have demonstrated that WAT is also an endocrine organ that contributes to energy homeostasis, not only through the storage or release of lipids, but also by secreting adipokines with effects in other tissues. Although hardly addressed, mitochondrial activity plays an important role in the white adipocyte physiology. Indeed, increased mitochondrial biogenesis is increased during the adipogenic process. Brown adipocytes are thermogenic cells that play an important role in maintaining the appropriate balance between energy storage and expenditure. They maintain this balance through normal mitochondrial function matching oxidative phosphorylation (OXPHOS) and dissipation of the proton gradient. Therefore, mitochondria in both adipose tissues, WAT and BAT, play key roles in metabolism. Excessive energy substrates, typically occurring in situations of obesity and metabolic syndrome, may lead to mitochondrial dysfunction with consequential effects on lipid and glucose metabolism.7 Moreover, abnormal mitochondrial function through increased ROS production in adipocytes results in lipid accumulation and insulin resistance. In this sense, patients with lipodystrophic syndromes, showing peripheral lipoatrophy, increased visceral WAT and insulin resistance, suffer from mitochondrial injury. Impaired mitochondrial function is also presented in HIV patients treated with highly active antiretroviral therapy (HAART), which leads to lipodystrophy and ectopic fat storage.8 On the other hand, patients with non-alcoholic steatohepatitis have also shown mitochondrial failure characterized by increased lipid peroxidation, alteration in mitochondria structure, depletion in mtDNA and low OXPHOS activity.9
Ageing is associated with obesity, alterations in body fat distribution and insulin resistance. Insulin resistance is often observed in elderly people with reduced OXPHOS activity similarly to obese patients with high risk for type 2 diabetes. Studies in mice with a defective catalytic subunit of mtDNA polymerase develop a phenotype associated with reduced lifespan and premature onset of ageing-related phenotype, with reduced subcutaneous fat and increased lipid accumulation in non-fatty tissues.10
In all these situations, treatments with targeted action on adipose tissue, more specifically in the mitochondria, increasing their oxidative capacity could have beneficial effects. The high oxidative capacity of BAT is due to its high mitochondrial density, expression of fatty acid oxidation enzymes and respiratory chain components, similarly to the muscle.11 Since the identification of discrete areas containing metabolically active BAT in adult humans, promoting proliferation and differentiation of brown fat cell precursors or by inducing white-to-brown fat trans-differentiation, could not only be useful to address the problem of obesity, but to also prevent the side effects associated with obesity.12
Section snippets
Mitochondrial activity in white and brown adipocyte biology
The functions of the adipocyte can be classified in three aspects. Firstly, its contribution to lipid metabolism: adipocytes take up free fatty acids and convert them into triglycerides for long-term storage. Secondly, adipocytes break down triglycerides into fatty acids and glycerol via lipolysis for release into blood during periods of energetic need. Finally, since diverse molecules secreted by WAT such as leptin, TNF-α, adiponectin, resistin and others are related to the degree of obesity
Mitochondrial dysfunction in adipocytes
Experimental evidence tends to incriminate the malfunction of adipose mitochondria in obesity and T2D. Mitochondria activity impairment in adipocytes is usually associated with reduced fatty acid β-oxidation, leading to an increase in cytosolic free fatty acids that alter glucose uptake.
Mitochondrial dysfunction increases endoplasmic reticulum stress and reduces adiponectin transcription by a pathway depending on the activation of c-Jun-NH2-terminal kinases and of activating transcription
Different treatments of disease with mitochondria of adipose tissue as target
The gradual acceleration of the obesity epidemic suggests that efforts made to control it through public health and drug initiatives are not necessarily working. Therapies to counter obesity are currently based on stimulating anorexigenic signals in the central nervous system to suppress appetite or inhibit the absorption of nutrients in the intestine. Despite the increased efforts to understand the relationship between fat, diabetes and cardiovascular risk factors, there are only a small
Summary
The study of the adipocyte offers new challenges to be able to explore the metabolic problems associated with the development of obesity and age-derived complications. Excess of adipose tissue is accompanied by an increase in the risk of developing insulin resistance and type 2 diabetes. However, the total or partial absence of adipose tissue or fat accumulation in other tissues, together with the toxic process called lipotoxicity, is also associated with an increase in the risk of metabolic
Acknowledgements
I thank Manuel Ros and Christopher Lelliott for their help in the preparation of the review.
I thank the funding bodies that give support for research within our laboratory: Ramon y Cajal programme from Ministerio de Ciencia e Innovacion (MICINN), MICINN BFU2009-10006, CCG10-URJC/BIO-560 and CAM (S2010/BMD-2423) from Comunidad de Madrid.
References (96)
- et al.
Adipose tissue as a therapeutic target in obesity
Endocrinología y Nutrición
(2009) - et al.
Special issue on lipotoxicity
Biochimica et Biophysica Acta
(2010) - et al.
Adipose tissue expandability, lipotoxicity and the metabolic syndrome–an allostatic perspective
Biochimica et Biophysica Acta
(2010) - et al.
Mitochondrial (dys)function in adipocyte (de)differentiation and systemic metabolic alterations
American Journal of Pathology
(2009) - et al.
PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro
Molecular Cell
(1999) - et al.
PPAR gamma is required for placental, cardiac, and adipose tissue development
Molecular Cell
(1999) - et al.
A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis
Cell
(1998) - et al.
Peroxisome proliferator-activated receptor gamma coactivator 1beta (PGC-1beta ), a novel PGC-1-related transcription coactivator associated with host cell factor
Journal of Biological Chemistry
(2002) - et al.
Acquirement of brown fat cell features by human white adipocytes
Journal of Biological Chemistry
(2003) - et al.
Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1alpha null mice
Cell
(2004)