Parathyroid hormone stimulates adipose tissue browning

Abstract

Purpose studying organ-to-organ communications (i.e., crosstalk) uncovers mechanisms regulating metabolism in several tissues. What is missing is identification of mediators of different catabolic conditions contributing to losses of adipose and muscle tissues. Identifying mediators involved in organ-to-organ crosstalk could lead to innovative therapeutic strategies since several disorders such as chronic kidney disease (CKD), cancer cachexia and other catabolic conditions share signals of worsening metabolism and increased risk of mortality. Recent Findings a recent breakthrough published in Cell Metabolism leads to the conclusion that parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP) cause “browning” of white adipose tissue (WAT) plus energy production via activation of uncoupling protein-1 (Ucp1). Browning was associated with muscle wasting in mouse models of cancer and CKD. The pathway to browning includes PTH/PTHrP-activation of protein kinase A (PKA) and lost muscle mass via the ubiquitin proteasome proteolytic system (UPS). Summary the results suggest that crosstalk between muscle and fat contributes in a major way to tissue catabolism. The pathway initiated by PTH or PTHrP is novel and it suggests potential interrelationships that control metabolism in other catabolic conditions. Identifying how the parathyroid hormone-PKA-UPS axis relates to obesity, type 2 diabetes and other insulin resistant conditions remains unclear.

ACVR2B/Fc counteracts chemotherapy-induced loss of muscle and bone mass

“…Indeed, the 2-year chronic administration of teriparatide, or rhPTH(1–34), a synthetic agonist of human PTH currently under investigation for the treatment of postmenopausal osteoporosis, was shown to potentially impact carcinogenicity by causing the formation of osteosarcomas in F344 rats, although the same finding has not been reported in the clinical setting thus far 82 , 83 . Moreover, despite their beneficial effects on bone mass, PTH and PTH-related protein (PTHrP) have been described to affect muscle size through the common PTH receptor (PTHR) 28 – 30 , therefore raising concerns that the administration of PTH peptide in patients with cancer or treated with chemotherapy, that are already at risk of significant muscle loss, may instead exacerbate their cachectic condition. Overall, it is known that muscle targeted pro-anabolic strategies can improve survival and quality of life in cancer 31 , 32 , as well as reduce the toxicity of anticancer drugs 17 , 36 .…”

“…bisphosphonates and denosumab, are approved for the prevention of bone loss in combination with cancer or chemotherapy, although issues related to limited efficacy and long-term side effects have been reported in some cases 27 . Similarly, other compounds, such as the parathyroid hormone (PTH) and PTH-related protein (PTHrP) peptides, are currently being tested, while their limited applicability in association with cancer still needs to be clarified 28 – 30 .…”

Joint and muscle involvement in primary hyperparathyroidism

“…Недавно было показано, что путь, ответственный за развитие мышечной дистрофии у мышей, ассоциирован с РТН1R. Стимуляция рецептора приводит к опосредованной активации протеинкиназы А, ассоциированной с расщеплением жировой ткани и экспрессией генов, связанных с мышечной атрофией [72].…”

Racial and Ethnic Disparities in the Obesity Paradox

“…16,17 Furthermore, browning of white adipose tissue has been shown to occur in a mouse model of CKD, thereby leading to inefficient energy expenditure and increased risk for cachexia/wasting. 18,19 Therefore, it is possible that patients with higher BMI have mechanisms in place that prevent inefficient energy expenditure and browning of white adipose tissue, thereby reducing their risk for cachexia. For instance, overactivity of the endocannabinoid system, a key player in physiologic energy preservation, can increase the risk for obesity while also preventing brown adipose tissue formation and pathogenesis of wasting/cachexia.…”

“…21 Many of these factors can be interrelated, with one causing and being caused by the other. For instance, in maintenance HD patients, inflammation, as indicated by higher C-reactive protein Browning of white adipose tissue may result in inefficient energy use and increased risk for wasting/cachexia 18,19 ; possible mechanisms may involve the endocannabinoid system, which plays a role in energy preservation 20 To be determined…”