Adipogenesis regulates adipose tissue expansion and function [7]. Despite the well-known role of PTHrP in the differentiation programming of stem cells into different cellular linages, its role in the regulation of adipogenic differentiation by human fat tissue-derived stem cells has only been partially elucidated at the gene expression level. Roca-Rodriguez et al. [8] showed that PTHrP was expressed in both visceral and subcutaneous adipose tissue in humans. Moreover, PTHRP expression progressively decreased during adipogenesis from undifferentiated mesenchymal cells. As a confirmation, data collected after PTHRP silencing in adipogenesis-committed stem cells demonstrated the downregulation of the adipogenic markers PPARG2, FABP4, ADRP, and CEBPA, coding for peroxisome proliferator activated receptor γ, fatty acid-binding protein 4, lipid droplet-associated adipose differentiation-related protein, and transcription factor CCAAT enhancer-binding protein α, respectively. Furthermore, they showed that PTHRP expression correlated with obesity-related morbidities, such as the setting of insulin resistance and the increase in body mass index and hip circumference in patients affected by type 2 diabetes, thereby defining PTHrP as a key regulator of their development. The mechanism via which PTHrP may switch the differentiation of stem cells from adipo- to osteogenesis, thereby inhibiting fat tissue formation, was studied in the rodent pluripotent mesenchymal cell line C3H10T^1⁄2. Co-exposure of cells to bone morphogenetic protein-2 (BMP2) and PTHrP determined the downregulation of PPARγ and aP2 (adipocyte fatty acid-binding protein) and the concurrent upregulation of alkaline phosphatase, type I collagen, and osteocalcin mRNA levels. The PKC-mediated signalization was found to be at least in part implicated in this activity [9].

Dealing with bone-adipose tissue endocrine interplay, Zhang et al. [10] demonstrated that, in Ptch1^c/c;HOC-Cre mutant mice, characterized by the perturbation of energy metabolism, the upregulated Hedgehog signalization increased bone-derived PTHrP release. This, in turn, triggered the modulation of the PKA/cAMP and Akt/Foxo pathways, leading to the overexpression of UCP1, coding for the uncoupling protein-1 that mediates energy expenditure via thermogenesis, with subsequent white adipose tissue (WAT) browning and enhancement of heat production. Moreover, PTHrP determined the increase of adiponectin mRNA and protein levels [10]. Adiponectin is involved in glucose homeostasis, because of its insulin-sensitizing activity [11,12], thereby indicating that PTHrP is also involved in the regulation of energy metabolism at this level. Since skeletal muscles also contribute to energy metabolism, it was also proven that in the mutant mice they underwent atrophy and adiponectin-triggered increase of fatty acid via significant upregulation of the genes whose products are involved in fatty acid oxidation (ACO, CPT1, and FABP3) and glucose uptake (GLUT1 and GLUT4). The action of adiponectin was mediated by the activation of 5′-AMP-activated protein kinase (AMPK); moreover, in the mutant mice AMPK was also activated in the liver in which the expression of GLUT1 was markedly increased. Therefore, in this experimental model, PTHrP, along with adiponectin’s contribution, was responsible for hypoglycemia due to glucose uptake and systemic fatty acid oxidation. As further support for this evidence, PTHrP was also found implicated in the higher rate of oxygen consumption and waste of fat and muscle tissues occurring in the Lewis lung carcinoma model of cancer cachexia developed in syngeneic C57BL/6 mice [13]. In particular, PTHrP (1–34), released among the tumor-derived factors, was proven to stimulate thermogenic gene expression, specifically upregulating UCP1 and DIO2, the latter coding for type 2 iodothyronine deiodinase, a selenoenzyme which increases during cold stress only in brown adipose tissue, ultimately resulting in the onset of hypermetabolism [14].

A recent study by Qin and colleagues [15] highlighted the role of PTHrP in both opposing brown adipose tissue (BAT) whitening and promoting WAT browning in mice transduced with adeno-associated PTHrP-encoding virus vector, submitted to a high-fat diet (HFD) for some weeks. PTHrP was found to protect the animals from the diet–induced onset of obesity stimulating WAT transdifferentiation and maintenance of BAT via upregulation of UCP1, UCP2, and PGC1α, the latter coding for PPARγ coactivator 1α. Moreover, VEGFA, coding for vascular endothelial growth factor A, was upregulated and considered responsible of the concomitant state of inflammation in BAT. In parallel, in the liver of HFD-submitted mice, overexpression of PTHrP was proven not only to attenuate the transcription level of the genes coding for enzymes and receptors responsible of fatty acid synthesis (ACSL1, FASN, and PPARG) but also to enhance that of lipolysis-related enzymes and receptors (ATGL, ACOX1, CPT1A, and PPARA). In addition, FGF21, coding for fibroblast growth factor 21, an atypical member of FGF family active on glucose and lipid metabolism [16] and on adiponectin production, was prominently upregulated in the liver of PTHrP-overexpressing mice, thereby resulting beneficial for the mitigation of the obesity-linked metabolic diseases such as hepatic steatosis, insulin resistance, and glucose intolerance.