Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia

Nature (Impact Factor: 41.46). 07/2014; 513(7516). DOI: 10.1038/nature13528
Source: PubMed


Cachexia is a wasting disorder of adipose and skeletal muscle tissues that leads to profound weight loss and frailty. About half of all cancer patients suffer from cachexia, which impairs quality of life, limits cancer therapy and decreases survival. One key characteristic of cachexia is higher resting energy expenditure levels than in healthy individuals, which has been linked to greater thermogenesis by brown fat. How tumours induce brown fat activity is unknown. Here, using a Lewis lung carcinoma model of cancer cachexia, we show that tumour-derived parathyroid-hormone-related protein (PTHrP) has an important role in wasting, through driving the expression of genes involved in thermogenesis in adipose tissues. Neutralization of PTHrP in tumour-bearing mice blocked adipose tissue browning and the loss of muscle mass and strength. Our results demonstrate that PTHrP mediates energy wasting in fat tissues and contributes to the broader aspects of cancer cachexia. Thus, neutralization of PTHrP might hold promise for ameliorating cancer cachexia and improving patient survival.

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Available from: Lawrence Kazak, Jul 28, 2014
    • "PTHrP is a potent inducer of thermogenic gene expression (Kir et al., 2014). PTHrP and PTH are similar in that they share sequence homology in their first 34 residues and, in all cases studied to date, act on the same cell surface receptor. "
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    ABSTRACT: Cachexia is a wasting syndrome associated with elevated basal energy expenditure and loss of adipose and muscle tissues. It accompanies many chronic diseases including renal failure and cancer and is an important risk factor for mortality. Our recent work demonstrated that tumor-derived PTHrP drives adipose tissue browning and cachexia. Here, we show that PTH is involved in stimulating a thermogenic gene program in 5/6 nephrectomized mice that suffer from cachexia. Fat-specific knockout of PTHR blocked adipose browning and wasting. Surprisingly, loss of PTHR in fat tissue also preserved muscle mass and improved muscle strength. Similarly, PTHR knockout mice were resistant to cachexia driven by tumors. Our results demonstrate that PTHrP and PTH mediate wasting through a common mechanism involving PTHR, and there exists an unexpected crosstalk mechanism between wasting of fat tissue and skeletal muscle. Targeting the PTH/PTHrP pathway may have therapeutic uses in humans with cachexia.
    No preview · Article · Dec 2015 · Cell metabolism
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    • "For instance, blockade of IL6 or BAT denervation significantly impaired cachexia-associated beige adipocyte biogenesis (Petruzzelli et al., 2014). In addition , Parathyroid hormone-related protein (PTHrP) derived from the Lewis lung carcinoma potently promotes beige adipocyte biogenesis (Kir et al., 2014). High level of serum PTHrP is associated with lean body mass in cachectic mice and humans. "
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    ABSTRACT: Since brown adipose tissue (BAT) dissipates energy through UCP1, BAT has garnered attention as a therapeutic intervention for obesity and metabolic diseases including type 2 diabetes. As we better understand the physiological roles of classical brown and beige adipocytes, it is becoming clear that BAT is not simply a heat-generating organ. Increased beige fat mass in response to a variety of external/internal cues is associated with significant improvements in glucose and lipid homeostasis that may not be entirely mediated by UCP1. We aim to discuss recent insights regarding the developmental lineages, molecular regulation, and new functions for brown and beige adipocytes.
    Full-text · Article · Oct 2015 · Cell metabolism
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    • "A recent study has found that the thermogenic program is activated in fat cells treated with the conditioned medium from Lewis lung carcinoma (LLC) cells, a well-characterized model of cachexia (Kir et al. 2014). Global gene expression analysis of LLC cells identified parathyroid hormone-related protein (PTHrP) as regulating the activation of thermogenesis, probably through the cAMP/PKA pathway (Kir et al. 2014). This discovery has begun to provide mechanistic insights into the etiology of the development of cachexia and further studies may suggest treatments that can prevent tissue wasting during disease. "
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    ABSTRACT: Obesity and its associated metabolic diseases present a major public health problem around the world. The discovery that thermogenic fat is active in adult humans has sparked a renewal of interest in the study of its development and function and in the feasibility of using modulators of thermogenesis to work against obesity. In recent years it has been shown that there are at least two distinct types of thermogenic fat cells; brown and beige fat. In this review we discuss the transcriptional mediators of thermogenesis and the signaling molecules that regulate thermogenic cells. We also review the effects of thermogenic fat activation on whole body metabolic parameters and evaluate the increasing evidence that activating thermogenesis in humans can be a viable method of ameliorating obesity. In these discussions we highlight targets that can potentially be stimulated or modified in anti-obesity treatments.
    Preview · Article · Mar 2015 · Journal of Endocrinology
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