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Previews be different from the human brain in this respect: connector hubs in the mouse appear to mostly use oxidative phosphorylation, a greater source of ATP than AG. This interpretation lends support to Raichle and colleagues’ assertion that the human brain is neotenous relative to other species. Goyal et al. suggest that the reduction in AG with age may result in reduced protection from oxidative stress, making high-AG regions especially vulnerable to diseases of aging. Highly connected regions of the brain appear to be especially vulnerable to a host of disparate neurodegenerative conditions (Crossley et al., 2014). While there are several potential explanations for the vulnerability of hubs, the work presented by Goyal et al. suggests that loss of energy supply is not likely, as CMRO2 did not decline with age; indeed, the relative reduction in AG with age should actually be accompanied by a greater supply of ATP to connector hubs, resulting from a shift to oxidative phosphorylation. On the other hand, an age-related reduction in AG might lead to reduced potential for synaptic plasticity and impaired ability of cells to deal with damaging reactive oxygen species. Previous work by this group showed that areas with a high glycolytic index in youth were especially vulnerable to amyloid deposition in adults with or without Alzheimer’s disease (Vlassenko et al., 2010).
Altogether, this body of work leads to tantalizing new questions. Why does AG decline with age, and is reduced synaptic plasticity its cause or consequence? Might the decline in AG provide a link between cerebrovascular disease, dementia, and aging? Does AG fluctuate dynamically: for example, does it increase when learning entails synaptic plasticity (Shannon et al., 2016), and what is the relative role of neurons and astrocytes in these processes (Magistretti and Allaman, 2015)? Magistretti and colleagues have suggested that AG, the metabolism of glucose to lactate, occurs almost exclusively in astrocytes. Interestingly, blocking the transfer of lactate from astrocytes to neurons abolishes memory consolidation (Suzuki et al., 2011). While a causal link between AG and brain neoteny has yet to be demonstrated, the series of papers by Raichle and colleagues opens up a fascinating avenue of research on the interplay between energetics and brain topology and their relation to human evolution and ontogeny. REFERENCES Bullmore, E., and Sporns, O. (2012). Nat. Rev. Neurosci. 13, 336–349. Crossley, N.A., Mechelli, A., Scott, J., Carletti, F., Fox, P.T., McGuire, P., and Bullmore, E.T. (2014). Brain 137, 2382–2395.
Fulcher, B.D., and Fornito, A. (2016). Proc. Natl. Acad. Sci. USA 113, 1435–1440. Gould, S.J. (1977). Ontogeny and Phylogeny (Belknap Press). Goyal, M.S., Hawrylycz, M., Miller, J.A., Snyder, A.Z., and Raichle, M.E. (2014). Cell Metab. 19, 49–57. Goyal, M.S., Vlassenko, A.G., Blazey, T.M., Su, Y., Couture, L.E., Durbin, T.J., Bateman, R.J., Benzinger, T.L.-S., Morris, J.C., and Raichle, M.E. (2017). Cell Metab. 26, this issue, 353–360. Magistretti, P.J., and Allaman, I. (2015). Neuron 86, 883–901. Oh, S.W., Harris, J.A., Ng, L., Winslow, B., Cain, N., Mihalas, S., Wang, Q., Lau, C., Kuan, L., Henry, A.M., et al. (2014). Nature 508, 207–214. Shannon, B.J., Vaishnavi, S.N., Vlassenko, A.G., Shimony, J.S., Rutlin, J., and Raichle, M.E. (2016). Proc. Natl. Acad. Sci. USA 113, E3782– E3791. Somel, M., Franz, H., Yan, Z., Lorenc, A., Guo, S., Giger, T., Kelso, J., Nickel, B., Dannemann, M., Bahn, S., et al. (2009). Proc. Natl. Acad. Sci. USA 106, 5743–5748. Suzuki, A., Stern, S.A., Bozdagi, O., Huntley, G.W., Walker, R.H., Magistretti, P.J., and Alberini, C.M. (2011). Cell 144, 810–823. Vaishnavi, S.N., Vlassenko, A.G., Rundle, M.M., Snyder, A.Z., Mintun, M.A., and Raichle, M.E. (2010). Proc. Natl. Acad. Sci. USA 107, 17757– 17762. Vlassenko, A.G., Vaishnavi, S.N., Couture, L., Sacco, D., Shannon, B.J., Mach, R.H., Morris, J.C., Raichle, M.E., and Mintun, M.A. (2010). Proc. Natl. Acad. Sci. USA 107, 17763–17767.
Burning Fat and Building Bone by FSH Blockade Carlos Henrique Sponton1,2 and Shingo Kajimura1,* 1Diabetes
Center and Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA and Comorbidities Research Center—OCRC, University of Campinas (UNICAMP), Campinas, Sao Paulo, Brazil *Correspondence:
[email protected] http://dx.doi.org/10.1016/j.cmet.2017.07.018 2Obesity
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., 2017) 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 signifi-
cant 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., 2015). Current
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Figure 1. The Role of Follicle-Stimulating Hormone in Osteoclasts and Adipocytes (A and B) Follicle-stimulating hormone (FSH) activates FSH receptor (FSH-R) that is coupled to the inhibitory G protein (Gi). (A) In menopause, increased FSH levels in the circulation trigger several signaling pathways in osteoclasts, such as MEK/Erk, Akt, and NF-kB, leading to the activation of osteoclastogenesis and bone reabsorption. In adipocytes, activation of the Gi protein via FSH-R decreases cAMP levels and thermogenic gene expression. (B) When the FSH signaling is blocked by a neutralizing antibody, osteoclast activity and subsequent bone reabsorption are inhibited. In adipocytes, the FSH antibody also activates brown/ beige fat thermogenesis through promoting UCP1 expression.
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., 2016). 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., 2017). 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., 1997), 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 FSHFSH-R signaling in bone (osteoclasts) promotes osteoclastogenesis and increased 286 Cell Metabolism 26, August 1, 2017
bone reabsorption in a menopause mouse model (Sun et al., 2006). Like osteoclasts, adipocytes also express FSH-R (Cui et al., 2012; Liu et al., 2015); it has been demonstrated that the activation of FSH-R stimulates lipid biosynthesis and increases fat storage (Liu et al., 2015), 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., 2017). To test this hypothesis, the authors examined the metabolic phenotype in mice treated with a polyclonal neutralizing antibody targeting the b-subunit of FSH. Following daily treatment with the FSHb 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 FSHb antibody in ovariectomized mice. The authors found that the blockade
of FSH signaling by the FSHb 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 FSHb antibody-treated mice. Since the effect of the FSHb 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 FSHb 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., 2015). 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
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Previews (Galmozzi et al., 2014), and PhAMexcised mouse, a model for mitochondrial content (Pham et al., 2012), the authors further demonstrated that FSHb antibody treatment robustly increased UCP1 expression and mitochondrial content in BAT. Notably, the FSHb 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 FSHb. 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, 2015). While the FSH blockade by the FSHb 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.
REFERENCES Cui, H., Zhao, G., Liu, R., Zheng, M., Chen, J., and Wen, J. (2012). J. Lipid Res. 53, 909–917. Davis, S.R., Lambrinoudaki, I., Lumsden, M., Mishra, G.D., Pal, L., Rees, M., Santoro, N., and Simoncini, T. (2015). Nat. Rev. Dis. Primers 1, 15004. Galmozzi, 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., and Kajimura, S. (2014). Cell Rep. 9, 1584–1593. Giordano, A., Frontini, A., and Cinti, S. (2016). Nat. Rev. Drug Discov. 15, 405–424. Liu, 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. (2015). Aging Cell 14, 409–420. Liu, 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. (2017). Nature 546, 107–112. Pham, A.H., McCaffery, J.M., and Chan, D.C. (2012). Genesis 50, 833–843. Sidossis, L., and Kajimura, S. (2015). J. Clin. Invest. 125, 478–486. Simoni, M., Gromoll, J., and Nieschlag, E. (1997). Endocr. Rev. 18, 739–773. Sun, 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. (2006). Cell 125, 247–260.
What’s So Special about FGF19—Unique Effects Reported on Skeletal Muscle Mass and Function David J. Glass1,* 1Novartis Institutes for Biomedical Research, 181 Massachusetts Avenue, Cambridge, MA 02139, USA *Correspondence:
[email protected] http://dx.doi.org/10.1016/j.cmet.2017.07.017
In a recent study published in Nature Medicine, Benoit et al. (2017) reported unique effects of FGF19 on mouse skeletal muscle: FGF19 induced skeletal muscle hypertrophy and blocked muscle atrophy, acting via FGF receptors and ßKlotho, while a related FGF21 hormone was ineffective. Most FGFs are cell-bound or matrixbound, anchored by binding to heparan-sulfate proteoglycans. The hormonal FGFs, FGF19 (FGF15 in the mouse), FGF21, and FGF23, are the exception— rather than binding to heparan sulfates, they heterodimerize to distinct Klotho proteins (Cuevas-Ramos and Aguilar-Salinas, 2016; Fukumoto, 2008). The Klothos (there are two: aKlotho and bKlotho) alter-
natively can be thought of as co-receptors or co-ligands for these hormonal FGFs, since they can either be cell-bound or released from their transmembrane domain by cleavage, and thus freed to circulate in the blood. Both FGF19 and FGF21 interact with bKlotho, and are thereby able to activate the same set of FGF receptors (FGFRs) (Ge et al., 2012), although there may be different affinities
of FGF19 versus FGF21 on FGFR1c versus FGFR4. In contrast, FGF23 interacts with aKlotho and regulates aging and phosphate metabolism (Shimada et al., 2004). FGF19 regulates bile acid metabolism and metabolic homeostasis (Degirolamo et al., 2016). To explore its potential effects in skeletal muscle, Benoit et al. (2017) treated mice for 7 days with a daily
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