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Departments of Pharmacology (A.M.S.) and Metabolic Disorders (R.W.M.) Merck Research Laboratories Rahway, New Jersey 07065
Address all correspondence and requests for reprints to: Alison M. Strack, RY80Y-145, Department of Pharmacology, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065. E-mail: alison_strack{at}merck.com; or Robert W. Myers, RY50G-246, Department of Metabolic Disorders, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065. E-mail: robert_myers{at}merck.com.
Obesity and its related comorbidities, often encompassed in the metabolic syndrome, are expected to soon surpass tobacco smoking as the leading cause of preventable death (1). The key features of metabolic syndrome include abdominal obesity, dyslipidemia, insulin resistance with or without glucose intolerance, and increased blood pressure (2). Left unchecked, metabolic syndrome often progresses to overt type 2 diabetes and/or cardiovascular disease. A new weapon in the armamentarium of approaches to combat the growth of obesity, metabolic syndrome, and type 2 diabetes may be a member of the fibroblast growth factor (FGF) family of proteins, FGF19.
The article by Fu et al. (3) in this issue extends previous results from Genentech (4) that demonstrated decreased body weight and adiposity as well as increased energy expenditure in transgenic mice expressing human FGF19; in addition, resistance to both diet-induced obesity and insulin desensitization were observed. They now demonstrate comparable improvements in body weight, adiposity, and glucose and lipid endpoints with the transgenic FGF19 mice crossed into the more aggressive ob/ob (leptin depleted) and UCP-DTA (brown adipose tissue deficient) mouse models. These findings suggest that FGF19 might reduce adiposity and improve insulin sensitivity via mechanisms that are independent of leptin signaling and brown adipose tissue (BAT) thermogenesis, respectively. This is notable, given the limited prevalence and thermogenic importance of BAT in humans (5) and the ineffectiveness of exogenous leptin in treating human obesity (6). However, although the observations in transgenic models are interesting, the usual caveats apply regarding the biological sequelae of developmental adaptations to the expressed transgene. Furthermore, the transgenic approach cannot currently be extrapolated to human therapeutics.
By examining subchronic treatment with exogenous, human recombinant FGF19 (rFGF19) in mature, diet-induced obese (DIO) mice, the work of Fu et al. provides an important and exciting extension of the transgenic studies. The pharmacological phenotype is largely in agreement with the transgenic phenotype and is consistent with the concept that rFGF19 may provide a novel approach to the treatment of metabolic syndrome. In DIO mice treated with rFGF19, indices of dyslipidemia, hepatic steatosis, hyperinsulinemia, hyperleptinemia, and insulin sensitivity are improved, and body weight and adiposity are reduced. These effects are mediated, at least in part, by increases in metabolic rate and fatty acid oxidation. Paradoxically, the observed responses are not accompanied by compensatory increases in food intake, which typically ameliorate evoked reductions in body weight (7). The endpoints improved by treatment with rFGF19 are those that are typically aberrant in obesity, type 2 diabetes, and metabolic syndrome in humans. There is currently a major unmet need for safe and highly effective pharmacological agents that treat obesity or type 2 diabetes, let alone an agent that can impact both pathologies. Of the current treatments for type 2 diabetes, only metformin (and possibly acarbose) lead to even modest weight loss; most therapies, in fact, lead to weight gain (8). Thus, rFGF19 may be a boon for human therapeutics.
Given the apparent lack of requirement of leptin or brown adipose tissue to explain the rFGF19 effects, the authors propose that rFGF19 acts to inhibit acetyl CoA carboxylase 2 (ACC2) and/or stearoyl-coenzyme A desaturease-1 (SCD1), thus increasing fatty acid oxidation. The available data are consistent with, although not proof of, increased hepatic fatty acid oxidation. Based on reduced respiratory quotient measurements, fatty acid oxidation is elevated after subchronic treatment with rFGF19. However, direct evidence that rFGF19-mediates increases in hepatic fatty acid oxidation in vivo (e.g. measurements of 3H palmitate oxidation rate, increased hepatic ketone bodies) is currently lacking.
The role of ACC2 and/or SCD1 in the apparent increase in fatty acid oxidation in FGF19-treated mice is also inferred by changes in hepatic mRNA levels. Liver ACC2 mRNA is decreased acutely and subchronically with rFGF19 treatment. It is notable that the decrease in hepatic ACC2 mRNA occurs within hours, whereas the observed increase in metabolic rate is manifest after several days of treatment. One possible explanation for this temporal disconnect could be that ACC2 is a long-lived protein. rFGF19 effects on liver ACC2 protein, activity, and/or malonyl coenzyme A levels in vivo, or in hepatocytes in vitro, would provide important confirmation of the proposed mechanism for increasing fatty acid oxidation. If this hypothesis proves correct, it would further support the emerging concept that activation of fatty acid oxidation may have beneficial effects in animal models of obesity and type 2 diabetes that might translate to humans. Interestingly, the phenotype of the ACC2–/– mouse is similar to the FGF19 phenotype (9, 10). The actual role of ACC2 in mediating the effects seen with rFGF19 might be addressed experimentally by assessing whether rFGF19 fails to further increase metabolic rate or weight loss in the ACC2–/– mouse or in ACC inhibitor-treated animals (11). Similarly, a mouse treated with a carnitine palmitoyltransferase 1 inhibitor (12) should be refractory to rFGF19 stimulation of fatty acid oxidation if ACC2 is causally implicated.
Decreases in SCD1 mRNA in both the FGF19 transgene and mice treated for several days with rFGF19 implicate it as another potential modulator of FGF19 activity. Measurements of rFGF19 effects on liver SCD1 protein, activity, and/or the saturation index in vivo, or hepatocytes in vitro, would provide further support for the involvement of SCD1. Again, the overall phenotypes of the rFGF19-treated and transgenic mice support this hypothesis. The SCD-1–/– mice have a very similar metabolic profile: decreased body weight and adiposity, increased energy expenditure, and improved insulin and lipid parameters (13). Interestingly, transgenic FGF19 mice, ACC2–/–, and SCD-1–/– mice are all hyperphagic (4, 9, 13), but mice subjected to subchronic rFGF19 treatment are not (3). This may simply result from changes to feeding pathways that occur during development secondary to altered nutrient signaling or availability.
rFGF19 administration into the brain also increased metabolic rate in the animals. There are four known FGF receptors (FGFR1–4), all of which are expressed in the brain (14). Of these, only FGFR4, which is expressed in low levels in the brain (14, 15, 16, 17), is reported to bind FGF19 in vitro (18). Possibly related is the observation that either central or systemic administration of FGF1 results in increases in sympathetic nervous system activation and adrenomedullary stimulation (19). Both of these processes lead to increased metabolic rate. FGF1 binds to all the FGFRs with comparable affinity (20), and thus both FGF19- and FGF1-mediated metabolic rate increases may occur through the same mechanism. Again, ACC2 is a logical mediator for this activity because it is localized in the hypothalamic arcuate nucleus and the dorsomedial and ventromedial hypothalamus (21, 22). These areas are important for food intake, energy expenditure, and body-weight regulation.
Although results obtained with rFGF19 are encouraging, consideration of the use of FGF19 as a therapeutic agent for metabolic disorders (presumably requiring chronic dosing) raises obvious safety concerns. Historically, FGFs have been recognized for their potential to be tumorigenic (23). Initially, FGF19-mediated agonism of FGFR4 was suggested to have limited potential for mitogenic activity (18, 24). However, it is now clear that FGF19 transgenic mice develop hepatic adrenocarcinomas with age, and rFGF19-treated mice exhibit proliferation of hepatocytes (25). The mitogenic potential of FGF19 needs to be fully delineated and its mechanism established. In this regard, two lines of evidence suggest that FGFR4 may not be the only cognate mouse receptor for human FGF19. First, the FGFR4–/– mice have a phenotype that is only partially consistent with the FGF19 data. FGFR4–/– mice have no reported metabolic rate abnormalities, although they do have elevated cholesterol metabolism and bile acid synthesis (26), not unlike the profile generated by rFGF19 treatment. Second, and more importantly, unpublished observations (John, L. M., and T. A. Stewart) state that that FGFR4–/– mice have responsiveness to FGF19. Both these observations lead to speculation that FGF19 effects on metabolism and/or tumorigenicity may be mediated by interactions with receptor(s) other than FGFR4 at the high doses employed in these studies. An important question in this regard is whether the metabolic and tumorigenic activities are mediated by the same or distinct receptors. Dose-response studies might identify a therapeutic window between the desirable metabolic effects of rFGF19 and its undesirable proliferative effects. Establishing whether hepatic adrenocarcinoma formation occurs in the FGFR4–/– mice treated with rFGF19 might also be informative. In all studies reported to date, mice have been treated with human rFGF, which may lack specificity for mouse FGFR4 at the doses employed. Studies with the mouse homolog of human FGF19, purportedly FGF15 (27), might therefore be of interest. Alternatively, investigation of the effects of human rFGF19 in the primate should shed considerable light on the potential of rFGF19 as a therapeutic agent.
Irrespective of whether or not FGF19 succeeds as a novel therapy for one or more of the pathologies associated with metabolic syndrome, the work of Fu et al. (3) offers the opportunity to identify potential new targets for the treatment of metabolic disorders. Clearly, identifying the receptor(s) and the signaling pathway(s) by which FGF19 acts will be crucial to this endeavor. The availability of the FGF4R–/– mice and/or the use of two-hybrid technology may be helpful in this regard. Examining the use of FGF19 in additional mouse lines containing deletions of various metabolic enzymes and/or signaling pathway components could facilitate target identification. The observations with FGF19 suggest that other growth factors should be monitored as prospective therapeutic agents for metabolic disorders. Additional research on the metabolic consequences of growth factor administration should offer new opportunities to understand the biology of obesity and type 2 diabetes mellitus.
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Received March 22, 2004.
Accepted for publication March 23, 2004.
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