Basic ScienceEffect of leptin treatment on mitochondrial function in obese leptin-deficient ob/ob mice
Introduction
Obesity is a key risk factor for insulin resistance and type 2 diabetes mellitus [1] and is associated with hyperleptinemia [2]. Increased body fat mass is also correlated with elevated ectopic lipid accumulation in non-adipose tissues and concomitant insulin resistance [3]. Several lines of evidence highlight an important role of mitochondria in the development of insulin resistance and type 2 diabetes [4], [5], [6]. However, the direct relationship between an obesogenic lifestyle with physical inactivity and overnutrition, and the impact of these factors on mitochondrial function and density has yet to be determined [7], [8], [9].
Mitochondrial energy production is mainly regulated on a nuclear level and the activity is tailored to meet both fuel supply and energy demands specific to each tissue. Tissue-specific differences in mitochondrial function can also be influenced by specific mRNA expression or protein profiles, as well as posttranslational modifications [10], [11]. Previously, we have provided evidence for differential mitochondrial respiration patterns in liver and oxidative and glycolytic skeletal muscle from healthy lean mice [12]. In liver, oxidative phosphorylation and electron transfer system capacity was limited to less than 20% of the maximal capacity when complex I substrates were used. In contrast, the same oxygen fluxes accounted for more than 50% of this maximal capacity in both glycolytic and oxidative skeletal muscle. However, in absolute terms, oxidative phosphorylation in oxidative skeletal muscle is more than twice as high as that of glycolytic muscle [12]. This tissue specificity of mitochondrial function could also influence the adaption to pathological conditions such as obesity. In glycolytic muscle from leptin receptor-deficient obese db/db mice, mitochondrial respiration, as well as protein expression of mitochondrial markers, is increased [12], whereas, in oxidative muscle, the oxidative phosphorylation state and peroxisome proliferator-activated receptor γ coactivator 1α and mitochondrial transcription factor A (TFAM) protein levels are decreased [12]. Hence, the impact of hyperphagia, diet composition, or inactivity may influence mitochondrial function in a tissue-specific manner.
Leptin is primarily an adipose-derived hormone that modulates feeding behavior, and regulates thermogenesis and peripheral lipid oxidation [13], [14]. Leptin-mediated regulation of feeding occurs mainly at the level of the hypothalamus, while thermogenic and metabolic control is exerted through both central and peripheral signaling [13]. Lipid oxidation in peripheral tissues is stimulated through AMP-activated protein kinase (AMPK) signaling [15], [16]. Leptin also enhances lipid export from the liver, thereby reducing hepatic steatosis, presumably via inhibition of stearoyl-CoA desaturase-1 [17], [18], and modulates insulin sensitivity via crosstalk with the insulin signaling pathway [19], [20]. These effects are likely due to a normalization of circulating leptin levels, rather than a reduction in steatosis [17]. Thus, the integration of leptin signaling with pathways important for intracellular energy sensing and metabolic flexibility constitutes a link between whole-body, tissue, and cellular metabolic homeostasis.
In this study, we determined tissue-specific mitochondrial function in leptin-deficient ob/ob mice and the effect of leptin treatment in key tissues controlling whole-body metabolic homeostasis including liver and both glycolytic and oxidative skeletal muscle. We provide evidence that mitochondrial adaptations to leptin-deficient obesity and leptin replacement are tissue-specific. Moreover, these differences reflect the magnitude of the disturbances in metabolic regulation observed in the ob/ob mouse.
Section snippets
Reagents
Reagents were purchased from Sigma-Aldrich (St Louis, MO), unless stated otherwise.
Animal care
Experiments were approved by the animal ethical committee, Stockholm North, and conducted in accordance with regulations for protection of laboratory animals. We studied female and male ob/ob mice and lean (+/?) littermates, on a C57BL/6J background. The ob/ob mouse lacks the adipose-derived hormone leptin and is hyperphagic, obese, moderately hyperglycemic and severely hyperinsulinemic [14], [21]. Mice were kept
Effect of leptin treatment on whole-body metabolism and tissue-specific fuel storage
Five days of leptin treatment reduced body weight in ob/ob (P < 0.001) and lean (P < 0.05) mice, whereas body weight remained stable in saline-treated mice of either genotype (Fig. 1A). Accumulated food intake was reduced in leptin-treated ob/ob mice (P < 0.001), but unaltered in leptin-treated lean mice (Fig. 1B). Lean and fat mass was unchanged in saline-treated lean mice (Fig. 1C), while fat mass increased in saline-treated ob/ob mice during the treatment period (P < 0.05). Leptin treatment reduced
Discussion
Obesity is one of the main risk factors for the development of insulin resistance and type 2 diabetes [1]. Obesity is also strongly correlated with both hyperleptinemia [2] and reduced mitochondrial density and function [7], [8], [27]. Leptin is central in the regulation of energy homeostasis, and impairments in leptin action lead to obesity and insulin resistance. Although the molecular mechanisms underlying the development of insulin resistance in obesity remain incompletely resolved,
Authors contribution
MHH, researched data and wrote the manuscript. RZT, researched data. MB, researched data and reviewed/edited the manuscript. PMGR, researched data and reviewed/edited the manuscript. JRZ, wrote the manuscript. MHH, RZT, MB, PMGR, and JRZ approved the final version of the manuscript.
Funding
This work was supported by grants from the European Foundation for the Study of Diabetes, Swedish Research Council, Swedish Diabetes Association, Strategic Research Foundation (INGVAR II), the European Research Council, and Commission of the European Communities (Contract No. LSHM-CT-2004-005272 EXGENESIS).
Conflict of interest
The authors have nothing to disclose.
Acknowledgments
Current address for PMGR is Diabetes and Obesity Laboratory, Institut D’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, Esther Koplowitz Centre (CEK), Barcelona; and Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Spain. JRZ is the guarantor of this work and, as such, had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
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