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Burning Fat and Building Bone by FSH Blockade

2017; Cell Press; Volume: 26; Issue: 2 Linguagem: Inglês

10.1016/j.cmet.2017.07.018

1932-7420

Carlos H. Sponton, Shingo Kajimura,

Fatty Acid Research and Health

The rise of follicle-stimulating hormone (FSH) is a hallmark of menopause associated with osteoporosis and visceral adiposity. In Nature, Zaidi and colleagues (Liu et al., 2017Liu P. Ji Y. Yuen T. Rendina-Ruedy E. DeMambro V.E. Dhawan S. Abu-Amer W. Izadmehr S. Zhou B. Shin A.C. et al.Nature. 2017; 546: 107-112Crossref PubMed Scopus (211) Google Scholar) report that blocking FSH action reduces body fat by promoting brown/beige fat thermogenesis, potentially providing a new intervention for the treatment of menopause-related metabolic diseases. The rise of follicle-stimulating hormone (FSH) is a hallmark of menopause associated with osteoporosis and visceral adiposity. In Nature, Zaidi and colleagues (Liu et al., 2017Liu P. Ji Y. Yuen T. Rendina-Ruedy E. DeMambro V.E. Dhawan S. Abu-Amer W. Izadmehr S. Zhou B. Shin A.C. et al.Nature. 2017; 546: 107-112Crossref PubMed Scopus (211) Google Scholar) report that blocking FSH action reduces body fat by promoting brown/beige fat thermogenesis, potentially providing a new intervention for the treatment of menopause-related metabolic diseases. During the transition from a reproductive to a non-reproductive phase (menopause), many women experience significant physiological changes, including a decrease in bone mass and an increase in visceral adiposity. These changes are major risk factors for osteoporosis, obesity, diabetes, and cardiovascular diseases (Davis et al., 2015Davis S.R. Lambrinoudaki I. Lumsden M. Mishra G.D. Pal L. Rees M. Santoro N. Simoncini T. Nat. Rev. Dis. Primers. 2015; 1: 15004Crossref PubMed Scopus (225) Google Scholar). Current therapeutic interventions against menopause-related obesity and metabolic diseases present limited efficacy and are often associated with a broad range of side effects, including depression (Giordano et al., 2016Giordano A. Frontini A. Cinti S. Nat. Rev. Drug Discov. 2016; 15: 405-424Crossref PubMed Scopus (150) Google Scholar). Hence, a new class of therapeutic interventions is urgently needed to circumvent the adverse effects of current pharmacological therapies. In a recent study, Zaidi and colleagues begin to address this need as they report that blocking the action of follicule-stimulating hormone (FSH) by a polyclonal antibody potently activates brown/beige fat thermogenesis and reduces body fat mass in mice (Liu et al., 2017Liu P. Ji Y. Yuen T. Rendina-Ruedy E. DeMambro V.E. Dhawan S. Abu-Amer W. Izadmehr S. Zhou B. Shin A.C. et al.Nature. 2017; 546: 107-112Crossref PubMed Scopus (211) Google Scholar). A marked increase in circulating FSH levels, caused in part by a decline in circulating estrogen levels, has been implicated in the adverse physiological effects of menopause. While FSH and FSH receptor (FSH-R) have well-established roles in the regulation of sex hormone production in reproductive organs (Simoni et al., 1997Simoni M. Gromoll J. Nieschlag E. Endocr. Rev. 1997; 18: 739-773Crossref PubMed Scopus (719) Google Scholar), identification of FSH-R in tissues other than the ovary or the testis led to the notion that FSH has physiological functions beyond reproduction. For instance, the authors' group previously showed that the activation of FSH-FSH-R signaling in bone (osteoclasts) promotes osteoclastogenesis and increased bone reabsorption in a menopause mouse model (Sun et al., 2006Sun L. Peng Y. Sharrow A.C. Iqbal J. Zhang Z. Papachristou D.J. Zaidi S. Zhu L.L. Yaroslavskiy B.B. Zhou H. et al.Cell. 2006; 125: 247-260Abstract Full Text Full Text PDF PubMed Scopus (566) Google Scholar). Like osteoclasts, adipocytes also express FSH-R (Cui et al., 2012Cui H. Zhao G. Liu R. Zheng M. Chen J. Wen J. J. Lipid Res. 2012; 53: 909-917Crossref PubMed Scopus (70) Google Scholar, Liu et al., 2015Liu X.M. Chan H.C. Ding G.L. Cai J. Song Y. Wang T.T. Zhang D. Chen H. Yu M.K. Wu Y.T. et al.Aging Cell. 2015; 14: 409-420Crossref PubMed Scopus (102) Google Scholar); it has been demonstrated that the activation of FSH-R stimulates lipid biosynthesis and increases fat storage (Liu et al., 2015Liu X.M. Chan H.C. Ding G.L. Cai J. Song Y. Wang T.T. Zhang D. Chen H. Yu M.K. Wu Y.T. et al.Aging Cell. 2015; 14: 409-420Crossref PubMed Scopus (102) Google Scholar), which may contribute to the increased risk of metabolic diseases during menopause. Accordingly, Liu et al. hypothesized that blocking FSH action could reduce body fat mass (Liu et al., 2017Liu P. Ji Y. Yuen T. Rendina-Ruedy E. DeMambro V.E. Dhawan S. Abu-Amer W. Izadmehr S. Zhou B. Shin A.C. et al.Nature. 2017; 546: 107-112Crossref PubMed Scopus (211) Google Scholar). To test this hypothesis, the authors examined the metabolic phenotype in mice treated with a polyclonal neutralizing antibody targeting the β-subunit of FSH. Following daily treatment with the FSHβ antibody (or the goat IgG as control) for 8 weeks, the authors found that this treatment significantly prevented diet-induced body fat gain, while it increased bone mineral density in male and female mice. No change was seen in total body weight. This decrease in body fat mass was associated with increased whole-body thermogenesis. On the other hand, the antibody treatment did not affect either food intake or physical activity. To mimic menopause in mice, the authors next tested the effect of the FSHβ antibody in ovariectomized mice. The authors found that the blockade of FSH signaling by the FSHβ antibody increased whole-body energy expenditure, leading to a significant reduction in body fat mass. Importantly, haploinsufficient Fshr+/− mice recapitulated the metabolic phenotype (i.e., decreased adiposity) of the FSHβ antibody-treated mice. Since the effect of the FSHβ antibody was not observed in the haploinsufficient Fshr+/− mice, the metabolic improvement caused by the antibody treatment is specific to the FSH signaling blockade. The authors also demonstrated the metabolic benefits of the FSHβ antibody treatment in 8-month-old mice. How does the FSH blockade prevent bone loss while activating thermogenesis and reducing fat mass? In adipocytes, FSH-R is coupled to the inhibitory G protein (Gi), instead of the stimulatory G protein (Liu et al., 2015Liu X.M. Chan H.C. Ding G.L. Cai J. Song Y. Wang T.T. Zhang D. Chen H. Yu M.K. Wu Y.T. et al.Aging Cell. 2015; 14: 409-420Crossref PubMed Scopus (102) Google Scholar). That said, the authors showed that the FSH signaling activates the Gi protein, which led to a decrease in intracellular cAMP levels. Since adipose thermogenesis by brown fat and beige fat is highly dependent on the cAMP-signaling pathway and subsequent expression of uncoupling protein 1 (UCP1), the inhibition of the FSH signaling promotes UCP1 expression in adipocytes (Figure 1). Using ThermoMouse, a mouse model that allows for monitoring UCP1 expression in vivo (Galmozzi et al., 2014Galmozzi A. Sonne S.B. Altshuler-Keylin S. Hasegawa Y. Shinoda K. Luijten I.H. Chang J.W. Sharp L.Z. Cravatt B.F. Saez E. Kajimura S. Cell Rep. 2014; 9: 1584-1593Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar), and PhAMexcised mouse, a model for mitochondrial content (Pham et al., 2012Pham A.H. McCaffery J.M. Chan D.C. Genesis. 2012; 50: 833-843Crossref PubMed Scopus (126) Google Scholar), the authors further demonstrated that FSHβ antibody treatment robustly increased UCP1 expression and mitochondrial content in BAT. Notably, the FSHβ antibody treatment powerfully promoted the "browning" of WAT, i.e., the emergence of thermogenic beige adipocytes in the subcutaneous WAT. Together, these data provide compelling evidence that the activation of brown/beige fat thermogenesis by the FSH blockade can significantly prevent diet/menopause-related fat mass gain. Concerning the therapeutic applicability in humans, the authors developed a monoclonal antibody termed "HF2" that targets the human FSHβ. Consistent with the results from the polyclonal antibody studies, the authors confirmed the effect of HF2 on reducing adipose tissue mass and promoting brown/beige fat thermogenesis in mice. Thus, determining the efficacy of HF2 in fat mass in humans, particularly those in the postmenopausal period, will be an exciting future study. Emerging evidence in mice and human studies suggests that increases in BAT thermogenesis and the browning of WAT are closely linked to an improvement in systemic glucose and lipid homeostasis (Sidossis and Kajimura, 2015Sidossis L. Kajimura S. J. Clin. Invest. 2015; 125: 478-486Crossref PubMed Scopus (454) Google Scholar). While the FSH blockade by the FSHβ antibody powerfully activated brown/beige fat thermogenesis in mice, the antibody treatment did not improve either glucose tolerance or insulin tolerance in the present study. While the underlying mechanism remains unclear at this point, an exciting future avenue of research would be to determine the extent to which BAT and bone communicate with each other through still uncharacterized signaling pathways that may control systemic glucose and lipid homeostasis. In summary, Zaidi and colleagues provided compelling evidence that osteoporosis and visceral adiposity can be alleviated by pharmacological inhibition of the FSH signaling. The present study opens new doors for novel and complementary treatments addressing menopause-related osteoporosis and metabolic diseases.