Contributions of adipocyte lipid metabolism to body fat content and implications for the treatment of obesity
Introduction
In most mammals, adipose tissue can undergo hypertrophy, causing obesity, or pathological atrophy that leads to lipodystrophy. The obese state results from an imbalance between caloric intake and energy expenditure. Consequently, excess circulating fuel is mainly stored not only in adipose tissue but also in ectopic sites, such as liver (causing hepatosteatosis), muscle, pancreas and the kidneys. Excess triglyceride (TG) storage in these ectopic sites is clearly associated with insulin resistance, glucose intolerance, dyslipidemia and hypertension. Adipose metabolism acts to buffer nutrient excess in promoting lipid storage with increased adipogenesis and lipogenesis [1].
There are two morphologically distinct types of adipose tissue: the white adipose tissue (WAT) and the brown adipose tissue (BAT). The WAT is the predominant type, located in the subcutaneous region and distinct visceral regions surrounding the internal organs, such as the heart, intestine, kidneys, and gonads. The major function of WAT is storage of energy as TG within lipid droplets to supply the whole organism in time of energy restriction. Additionally, secretion of adipokines from WAT (i.e. adiponectin, leptin) regulates overall energy balance. The BAT exists in rodents and humans, with its primary role as a thermogenic organ. Brown fat in normal adult humans has recently been shown to be functional in terms of responsiveness to β-adrenergic stimulation and heat generation [2].
Strategies that aim to increase TG hydrolysis (lipolysis) and subsequent fatty acid utilization might be useful in ameliorating or preventing obesity. Such a strategy of inducing preferential TG utilization would be highly desirable to preserve lean mass, as weight loss is typically associated with an obligatory loss of lean mass owing to the inflexibility of substrate utilization [3, 4] Nevertheless, elevated circulating free fatty acid (FFA) concentrations have been associated with accumulations of TG in ectopic sites. Also, promoting increased fatty acid oxidation in skeletal muscle leads to myopathy [5•] and favoring cardiac lipid utilization results in cardiomyopathy [6]. Consequently, these observations suggest that a balance of substrate oxidation is critically important for the long term health of various tissues. A concomitant increase in the rate of fatty acid oxidation can compensate for the increase in fatty acid release from adipose tissue, preventing an increase in circulating FFA concentrations [7••]. Adipocyte fatty acid utilization is also triggered in some situations where WAT can acquire phenotypic and molecular features of BAT [8]. This phenotypic switch of WAT from an energy storing organ to an energy burning organ could be utilized as a therapeutic modality in disorders of energy balance and obesity.
Section snippets
Switching between TG storage to TG hydrolysis
With excess caloric intake and low physical activity, energy balance is tipped into storage mode and adipose tissue functions as the major energy storage organ. Within the adipocyte, FFAs are esterified into triglycerides that are packed into lipid droplets (Figure 1a). During times of increased energetic demand, WAT has the ability to switch to acting as a nutrient provider to the other organs [9••]. In this context, induction of lipolysis is the essential mechanism that triggers the breakdown
Brown adipose tissue and its function in the overall energetic balance
Historically, brown-fat tissue was mainly characterized in rodents and human infants. Combined positron-emission tomography and computed tomography (PET–CT) has been used to identify metabolically active adipose tissue with a high rate of uptake of 18F-fluorodeoxyglucose (18F-FDG) as putative brown adipose tissue in adult humans. As opposed to the white fat cells, brown adipocytes store lipids in multiple small lipid droplets (multilocular) and its main function is to participate in
Conclusions
Major therapies that are in development target the central control of satiety. However, caloric reduction is accompanied by reductions in both fat and lean mass, which in turn, may contribute to the reduction in resting metabolism in the formerly obese [4]. Additionally, reductions in both fat and lean mass rather than a specific loss of fat mass lowers the metabolic benefits of weight loss. Consequently, new therapies should target adipose tissue to specifically reduce fat mass. In this
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
This work was partly funded by RO1DK057621 and PO1DK26687.
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