Contributions of adipocyte lipid metabolism to body fat content and implications for the treatment of obesity

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Obesity is a chronic disease that increases susceptibility to various diseases, particularly cardiovascular dysfunction, type 2 diabetes, and some types of cancer. In this review, we highlighted recent evidence in mouse models that support a potential benefit of increasing adipose lipid utilization through stimulating lipolysis in adipose tissue and fatty acid oxidation. Brown adipocyte development within white adipose tissue of humans suggests that mouse models may be applicable to human obesity. Consequently, new therapies should target adipose tissue to specifically reduce fat mass through controlled triglyceride utilization.

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.

References (54)

  • P. Chakrabarti et al.

    Mammalian target of rapamycin complex 1 suppresses lipolysis, stimulates lipogenesis, and promotes fat storage

    Diabetes

    (2010)
  • C. Franco et al.

    Growth hormone treatment reduces abdominal visceral fat in postmenopausal women with abdominal obesity: a 12-month placebo-controlled trial

    J Clin Endocrinol Metab

    (2005)
  • K.G. Hofbauer

    Molecular pathways to obesity

    Int J Obes Relat Metab Disord

    (2002)
  • P. Seale et al.

    Transcriptional control of brown adipocyte development and physiological function—of mice and men

    Genes Dev

    (2009)
  • N. Levin et al.

    Decreased food intake does not completely account for adiposity reduction after ob protein infusion

    Proc Natl Acad Sci U S A

    (1996)
  • E.P. Weiss et al.

    Lower extremity muscle size and strength and aerobic capacity decrease with caloric restriction but not with exercise-induced weight loss

    J Appl Physiol

    (2007)
  • S. Levak-Frank et al.

    Muscle-specific overexpression of lipoprotein lipase causes a severe myopathy characterized by proliferation of mitochondria and peroxisomes in transgenic mice

    J Clin Invest

    (1995)
  • H. Yagyu et al.

    Lipoprotein lipase (LpL) on the surface of cardiomyocytes increases lipid uptake and produces a cardiomyopathy

    J Clin Invest

    (2003)
  • K. Jaworski et al.

    AdPLA ablation increases lipolysis and prevents obesity induced by high-fat feeding or leptin deficiency

    Nat Med

    (2009)
  • C. Guerra et al.

    Emergence of brown adipocytes in white fat in mice is under genetic control. Effects on body weight and adiposity

    J Clin Invest

    (1998)
  • M. Lafontan et al.

    Lipolysis and lipid mobilization in human adipose tissue

    Prog Lipid Res

    (2009)
  • C. Buettner et al.

    Leptin controls adipose tissue lipogenesis via central, STAT3-independent mechanisms

    Nat Med

    (2008)
  • R.E. Duncan et al.

    Regulation of lipolysis in adipocytes

    Annu Rev Nutr

    (2007)
  • K. Ahmed et al.

    An autocrine lactate loop mediates insulin-dependent inhibition of lipolysis through GPR81

    Cell Metab

    (2010)
  • R. Nogueiras et al.

    The central melanocortin system directly controls peripheral lipid metabolism

    J Clin Invest

    (2007)
  • M.N. Brito et al.

    Differential activation of the sympathetic innervation of adipose tissues by melanocortin receptor stimulation

    Endocrinology

    (2007)
  • D.L. Brasaemle et al.

    Perilipin A and the control of triacylglycerol metabolism

    Mol Cell Biochem

    (2009)
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