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INSULIN-GLUCAGON-GI PEPTIDES-DIABETES MELLITUS |
Departments of Molecular Biology (E.T., L.F., L.J., B.H., X.H., M.R., T.A.S.), Automation and Assay Technology (J.P.S., S.P.T.), Cardiovascular Research (L.P.-B.) and Pathology (D.F.), Genentech, Inc., South San Francisco, California 94080
Address all correspondence and requests for reprints to: Timothy A. Stewart, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080. E-mail: . tas{at}gene.com
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Abstract |
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Introduction |
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Energy expenditure occurs as a result of processes that allow for work, growth, reproduction, heat, and maintenance of homeostasis. Some aspects of energy expenditure can be regulated, and several hormones that contribute to this regulation have been identified. Thyroid hormone increases metabolic rate or energy expenditure by increasing the activity of several metabolic pathways (for review, see Ref. 5). Leptin ultimately activates sympathetic outflow from the hypothalamus and produces an increase in activity and mass of the brown adipose tissue (BAT) (6, 7). Whether this is the sole, or principal, means by which leptin increases energy expenditure has not been resolved.
Metabolic pathways that can operate in a cyclic pattern have the potential to be energetically very costly, and the appropriate regulation and compartmentalization of these pathways can have significant effects on energy utilization. For example, hepatocytes are capable of both synthesizing and oxidizing fatty acids, but multiple regulatory steps largely prevent this wasteful cycle. One of the more important of these steps governs the entry of fatty acids, via carnitine palmitoyl transferase 1 (CPT1), into the mitochondria (8, 9). The activity of CPT1 is regulated by malonlyl coenzyme A (CoA), and the importance of this pathway for regulating energy expenditure has been convincingly demonstrated in experiments in mice with a mutation in the gene encoding the mitochondrially associated form of acetyl CoA carboxylase (ACC2). These mice appear to be unable to synthesize the malonyl CoA required to inhibit CPT1. Under these conditions, there is an increased metabolic rate and a resistance to diet-induced obesity (10).
The fibroblast growth factor (FGF) proteins have been primarily associated with fibroblast and epithelial cell proliferation, and pattern formation (for review, see Refs. 11 and 12). More recently, however, it appears that some of the newly described FGFs may be more important for maintaining physiological homeostasis. Thus, FGF23 is an important regulator of serum inorganic phosphate levels (13). In addition, mice with a deficiency in FGF receptor-4 (FGFR4) have altered expression of genes, such as cholesterol-7-a-hydroxylase (Cyp7a) and 3-hydrox3-methylglutaryl-CoA reductase (HMG reductase), which are important for cholesterol and bile acid homeostasis (14). The recently described human FGF19 is unusual in that it has no detectable mitogenic activity and binds to only one of the known FGF receptors (FGFR4) (15). Here, we report that transgenic mice expressing human FGF19 had an increased metabolic rate and decreased adiposity and two potential mechanisms were identified.
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Materials and Methods |
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Transgenic mice
The human FGF19 cDNA (15) was ligated 3' to the pRK splice donor/acceptor site that was preceded by either the myosin light chain (16) or the metallothionein promoters (17). The FGF19 cDNA was also followed by the splice donor/acceptor sites present between the fourth and fifth exons of the human GH gene (18). The entire expression fragment was purified free from contaminating vector sequences and injected into one-cell mouse eggs derived from FVB X FVB matings. FGF19 transgenic mice were identified by PCR analysis of DNA extracted from tail biopsies. All transgenic mouse experiments used the inbred (FVB) transgenic mice, and the controls were nontransgenic littermates.
Indirect calorimetry
Oxygen consumption was measured in a Columbus Instruments Oxymax open circuit calorimeter (Columbus, OH).
Diet
Standard mouse chow was Purina 5010 (Harlan Teklab, Madison, WI). The high fat (58% kJ fat) and low fat (10.5% kJ fat) isocaloric diets were based on the diets described by Surwit and colleagues (19) and were purchased from Research Diets (New Brunswick, NJ).
Assays
Insulin and leptin were assayed by ELISA kits (Crystal Chem, Chicago, IL). Glucose was assayed either by LIFESCAN Fast Take glucose meter (Lifescan, Inc., Milpitas, CA) or the glucose oxidase method. All other hormones and serum metabolites were assayed by Anilytics, Inc. (Gaithersburg, MD). Bomb calorimetry of the food and feces for the metabolizable energy calculations was performed by Anilytics, Inc. Fat content in the muscle and liver was assayed using the extraction procedures of Folch et al. (20) and an enzymatic triglyceride reagent kit (Sigma, St. Louis, MO). Real time quantitative PCR using 100–500 ng total RNA was performed as described (21). Expression for each gene was determined, from the Ct values, relative to the expression of the ribosomal protein gene RPL19. The mean relative expression for the control mice set to 1.0 and the expression in the transgenic mice calculated relative to the control mice. Primers and probe sequences are available on request.
Glucose metabolism
Glucose tolerance tests (GTT) were performed by injecting each mouse with the same amount of glucose (35 mg glucose ip). As the transgenic mice weighed less than the control mice, the transgenic mice received more glucose as a function of body weight (approximately 1.4 mg glucose/g body weight) than the wild-type mice (approximately 1.2 mg glucose/g body weight). This relative increase in glucose dosing in the transgenic mice emphasizes the lower blood glucose levels seen in these mice. Conversely, insulin suppression tests (ISTs) were performed by injecting each mouse with 0.3 IU insulin/kg iv. Thus, in this case the transgenic mice received less total insulin than the wild-type controls, and again emphasizes the lower glucose levels seen in the transgenic mice. For both the GTT and the IST, whole blood glucose was measured at the indicated times using a LIFESCAN Fast Take glucose meter.
Temperature and activity
Core body temperature was monitored telemetrically by ip implanted Physiotel body temperature transmitter devices (Data Sciences International, St. Louis, MO). Activity was monitored via the analysis of the frequency with which the mice broke infrared beams that were placed one per inch (x- and y-axes).
Analysis
Unless otherwise noted all data are presented as the means plus and minus the standard deviations. Comparisons between transgenic and wild-type mice were made using an unpaired t test. Oxygen consumption is expressed as a function of body mass raised to the 0.75 power (22, 23, 24).
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Results |
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On standard lab chow, the transgenic mice weighed less than the control mice (Fig. 1A
). The difference was significant at 5 d for the male mice (Fig. 1A) and 31 d for the female mice (data not shown). The largest differences (both absolute and proportional) were obtained at 3–4 wk of age for both sexes. Analysis of body composition revealed that a primary reason for the decreased body weight was a significant reduction in fat content. This was seen with both total body composition analysis (Fig. 1B) and fat pad weights (Fig. 1C). There was no significant reduction in either protein or ash content (Fig. 1B) and (with the exception of the BAT, Fig. 4) the other major organs were proportional to body weight (Fig. 1C and data not shown).
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). Absorption was also not impaired. Calorimetric analysis of the food and feces indicated that the metabolizable energy for the transgenic mice (measured as protein and fat intake, or as energy content) was significantly greater for the transgenic mice (Fig. 2B).
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(for two independent lines of transgenic mice) demonstrated that both male and female transgenic mice had a higher VO2. This was most obvious during the night when mice are active and feeding. The effect of FGF19 was diminished during the light cycle. There was, however, no detectable difference in metabolic rate between fasted transgenic mice and fasted controls. There was no obvious change in respiratory quotient in the FGF19 transgenic mice (data not shown). The increase in metabolizable energy (Fig. 2
, A and B) with no increase in growth or storage (Fig. 1A) and the increase in VO2 (Fig. 3A) with no change in respiratory quotient, pointed to an increase in energy expenditure in the transgenic mice. This increase was reflected in a very small (approximately 0.2 C) increase in temperature as the mice approach the nadir of the diurnal rhythm (Fig. 3B). The three lowest readings taken in the control mice, and the corresponding values in the transgenic mice, are shown separately in the right panel of Fig. 3B. Activity analysis using a two-dimensional beam-breaking format indicates that there was no significant difference between the transgenic and the control mice with respect to coarse motor activity (Fig. 3C). Other than the decreased adiposity, the FGF19 transgenic mice were relatively normal. They were fertile and their hematological profile and serum electrolytes were normal (data not shown). Histological analysis indicated that all major organs were normal with the exception of the liver. In the older (greater than 5 months) transgenic mice, there were dysplastic changes in the liver (Nicholes, K., S. Guillet, E. Tomlinson, K. Hillan, B. Wright, G. D. Frantz, T. A. Pham, L. Dillard-Telm, S. P. Tsai, J.-P. Stephan, J. Stinson, T. Stewart, and D. M. French, manuscript in preparation).
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), and there was no thyroid hyperplasia (data not shown). Both GH and IGF-1 have also been implicated in maintaining body composition (27, 28). GH levels were not obviously altered (data not shown), whereas total IGF-1 was reduced (Table 1). Corticosterone was also not altered, but there was a reduction in glucagon (Table 1).
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). The BAT in the FGF19 transgenic mice appeared histologically normal (data not shown), suggesting that the increased relative size of the BAT may also translate into a relative increase in the activity of this organ. We also investigated the expression of the UCPs in the BAT. There was an approximately 4-fold increase in the expression of UCP2 (Fig. 4B). The expression of UCP 1, 3, 4, and 5 was not different in the transgenic mice compared with the controls.
For several reasons (see Discussion), we consider the liver as major target organ for FGF19. Thus, we have measured the mRNA levels, in the liver, of several metabolically important genes (Fig. 5A). We found that the expression of the genes for two important lipogenic enzymes (malic enzyme and stearoyl CoA desaturase) was significantly reduced in the transgenic mice (Fig. 5A). In addition, we found that there was a significant reduction in the expression of ACC2 (Fig. 5A). This enzyme appears to be a major regulator of the rate of entry of fatty acids into the mitochondria and mice genetically deficient in this enzyme have an increase in metabolic rate and a decrease in adiposity (10). We found no change in the expression of the insulin receptor, insulin receptor substrates 1 and 2, phosphotyrosine phosphatase 1B, CPT1, acetyl CoA carboxylase 1 (ACC1), and acyl CoA dehydrogenase, long (data not shown).
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). The muscles of the transgenic mice also had reduced triglyceride. We did not, however, see any change in expression of muscle ACC2 (data not shown); thus, the lower muscle triglyceride may be a secondary consequence of a reduction in total body fat.
FGF19 and diet induced obesity and diabetes
As the chow fed FGF19 transgenic mice have decreased fat content (Fig. 1), we investigated the effect of FGF19 expression on the response to a high fat diet (30). For both male (Fig. 6A) and female (data not shown) control mice (open symbols), there is a significant effect (P < 0.05) of the diet at 6 wk of age and older. In contrast, there is no discernible effect of the high fat diet on the transgenic mice (filled symbols, P > 0.1). After 12 wk on the high fat diet, the mice were killed and the weights of the internal organs determined. The most striking differences were in the white adipose depots (Fig. 6B). The fat pads from the transgenic mice (both males and females) weighed significantly less than the corresponding fat pads from the control littermates. Consistent with the lower adiposity (31), leptin levels in these high fat fed mice were also lower (Fig. 6C). As was found for the chow fed mice, the relative size of the liver (Fig. 6B), and other major internal organs (data not shown) were not different in the transgenic mice compared with the controls.
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). There is a significant (P < 0.05) effect of the diet in the control mice at all time points except for the final (180 min) value. For the transgenic mice, there is an apparent effect (P < 0.05) of the diet only at the 30-min time point. At all time points, the glucose levels in the transgenic mice were significantly less than the control mice (within diet comparisons). Further, the glucose levels in the high fat fed transgenic mice were lower than the chow fed control mice for all but two time points (15 and 30 min).
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; females have a similar response (data not shown)]. In these experiments there was also a greater proportional decrease. The mean glucose level in the control mice at 45 min was 43 ± 10% (mean ± SD) of the zero time point value whereas for the transgenic mice the comparable values were 31 ± 9 (P = 0.014). We also measured circulating insulin levels (Fig. 7C). The high fat diet led to a significant (P < 0.05) increase in random fed insulin levels in the control mice. The effect of the diet on the transgenic mice was not statistically significant (P > 0.05). On both diets the transgenic mice had significantly lower insulin levels than the control mice (P < 0.01 for both diets). These findings—the decreased glucose excursion seen in the GTT, the lower glucose levels attained in the IST, and the lower insulin levels—all point to a significant increase in insulin sensitivity in these transgenic mice. |
Discussion |
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As we have been unable to detect the expression of FGFR4 in adipocytes that have been extensively purified free from contaminating stromal cells (data not shown), it is likely that the decrease in adiposity is secondary to the increased metabolic rate (32).
The increase in food intake in the transgenic mice is also probably indirect. Decreased leptin (25, 33), insulin (34, 35), and CNS glucose utilization (36) all induce feeding behavior in mice, and circulating levels of leptin, insulin, and glucose are decreased in the transgenic mice.
The increase in insulin sensitivity in the transgenic mice may be an indirect consequence of the decrease in adiposity and tissue triglycerides. The relationship between insulin sensitivity and obesity (37, 38) and intramyocellular triglycerides (39) is now well established, and the FGF19 transgenic mice had a significant reduction in tissue (muscle and liver) triglycerides as well as the obvious decrease in adipose tissue. The decrease in liver triglycerides may be a direct consequence of the decreased ACC2 expression and the increased fatty acid oxidation that occurs with decreased ACC2 levels (10). Consistent with an indirect effect on insulin sensitivity through decreased adiposity, we did not detect differences in the expression of a number of genes implicated in mediating insulin signaling.
Mechanisms
For several reasons, we favor the possibility that the liver is a primary target for FGF19. First, the liver is a central organ in regulating carbohydrate and lipid metabolism and is responsible for a disproportionate amount (relative to body mass) of the standard metabolic rate (40). Further, in rats that have undergone a partial hepatectomy, there is a substantial loss of diet induced thermogenesis (41). Second, FGFR4, a reported receptor for FGF19 is highly expressed in liver (15) and hepatocytes (42). Although FGFR4 appears to be at least one receptor for FGF19, an altered metabolic rate was not reported in FGFR4 knockout mice (43); they do, however, have altered cholesterol metabolism (14), suggesting a role for this receptor in regulating lipid metabolism. Third, circulating levels of two liver markers (albumin and alanine amino transferase) were increased (males only, Table 1). Fourth histological changes were found in the livers of the older transgenic mice (Nicholes, K., S. Guillet, E. Tomlinson, K. Hillan, B. Wright, G. D. Frantz, T. A. Pham, L. Dillard-Telm, S. P. Tsai, J.-P. Stephan, J. Stinson, T. Stewart, and D. M. French, manuscript in preparation), as has been reported for mice with altered metabolism caused by deletions in the genes encoding Glut 2 (44) or the insulin receptor (45).
An increased metabolic rate could be achieved through an increased flux of fatty acids through the mitochondrial ß oxidation pathway. This process is normally regulated by both a mass action effect on a system that may be close to equilibrium and by substrate availability. Substrate availability is controlled by the transport of fatty acids (as carnitine esters) through the CPT1 (46) and the major regulator of CPT1 activity is malonyl CoA (8). Malonyl CoA is synthesized by acetyl CoA carboxylase, which exists in two isoforms (ACC1 and ACC2). The isoform responsible for regulating CPT1 activity is ACC2 (47). Thus, as ACC2 decreases (as occurs in the FGF19 transgenic mice), mitochondrially associated malonyl CoA levels decrease, CPT1 activity increases and there would be increased availability of fatty acids for ß oxidation. The importance of ACC2 with respect to fatty acid oxidation has been convincingly demonstrated in mice deficient for ACC2 (10). These mice are lean and do not become obese on a high fat diet. While the level of ACC2 is decreased in the FGF19 transgenic mice to approximately 40% of normal, it is not clear how this translates into malonyl CoA levels. Relevant to this is the observation that, even in the complete absence of ACC2, the level of total liver malonyl CoA was not detectably changed (10). This failure to detect changes in the total pool of malonlyl CoA presumably reflects the activity of ACC1 and the impact on CPT1 being via local (mitochondrial) production of malonyl CoA by ACC2. In contrast to the reduction of ACC2, FGF19 had no detectable effect on the expression of ACC1, the isoform apparently responsible for generating the malonyl CoA that is the precursor for fatty acid synthesis.
Another possible cause of the increased metabolic rate in the FGF19 transgenic mice is a change in the biology of the BAT and the associated UCPs (for review, see Ref. 48). A role for BAT in regulating body composition was demonstrated in mice in which there is genetic reduction of the BAT. These mice develop obesity and hyperphagia (29). We have found that the relative weight of the BAT was increased in the transgenic mice and the tissue appeared normal by both histological appearance and expression of the major uncoupling protein, UCP1. Although the BAT changes seen in the FGF19 transgenic mice were similar to those seen in rodents treated with norepinephrine (49) or with specific ß3 adrenergic receptor agonists (32), further analyses are required to determine whether the increase in BAT mass is causally related to the increase in metabolic rate. FGF16 is a mitogen for primary brown adipocytes (50), although the expression of this growth factor did not correlate with the BAT hyperplasia induced by cold exposure. Although FGF19 does not appear to be mitogenic (15), it is possible that this growth factor alters the differentiation of the brown adipocytes.
Mice with a genetically engineered reduction in BAT become obese (29). In contrast, mice deficient in the principal BAT uncoupling protein, UCP1, do not (51), suggesting that other mechanisms (possibly including the other UCPs) are important in the physiological functioning of this organ. In the BAT from the FGF19 transgenic mice, there was a disproportional increase in UCP2. The gene encoding UCP2 was identified as residing in a locus that controls obesity (52), and there is an inverse correlation between expression of this gene correlated with body fat in humans (53). While the normal physiological function of UCPs 2–5 is still unclear, transgenic overexpression of both UCP1 (54) and UCP3 (55) in muscle can prevent obesity.
Two plausible mechanisms for the increase metabolic rate have been described—an increase in BAT mass and a decrease in liver ACC2. How these components are woven together and the relative importance of each in the biology elicited by FGF19 will be of the subject of future studies.
Conclusion
The ability of FGF19 to increase metabolic rate and reduce adiposity is striking considering that few other changes are seen in these transgenic mice. Total body length was relatively unaffected, serum electrolytes were normal, and both males and females were fertile (data not shown). Histological examination of internal organs reveals that, in some transgenic mice that are older than 5 months, there were regions of liver dysplasia, whereas all other tissues were normal (data not shown). The specific effects of FGF19 may be related to the observation that FGF19 interacts only with FGFR4 (15) and that FGFR4 is not able to transmit a mitogenic signal (56). It will be of considerable interest to determine whether the increased metabolic rate and decreased adiposity can be elicited by systemic delivery of a recombinant protein.
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Acknowledgments |
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Footnotes |
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Received October 18, 2001.
Accepted for publication January 28, 2002.
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References |
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subunit knockout produces opposite effects on energy metabolism. J Clin Invest 105:615–623[Medline]
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J. Li, P. C. Pircher, I. G. Schulman, and S. K. Westin Regulation of Complement C3 Expression by the Bile Acid Receptor FXR J. Biol. Chem., March 4, 2005; 280(9): 7427 - 7434. [Abstract] [Full Text] [PDF]
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A. D. Gagliardi, E. Y. W. Kuo, S. Raulic, G. F. Wagner, and G. E. DiMattia Human stanniocalcin-2 exhibits potent growth-suppressive properties in transgenic mice independently of growth hormone and IGFs Am J Physiol Endocrinol Metab, January 1, 2005; 288(1): E92 - E105. [Abstract] [Full Text] [PDF]
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A. M. Strack and R. W. Myers Modulation of Metabolic Syndrome by Fibroblast Growth Factor 19 (FGF19)? Endocrinology, June 1, 2004; 145(6): 2591 - 2593. [Full Text] [PDF]
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L. Fu, L. M. John, S. H. Adams, X. X. Yu, E. Tomlinson, M. Renz, P. M. Williams, R. Soriano, R. Corpuz, B. Moffat, et al. Fibroblast Growth Factor 19 Increases Metabolic Rate and Reverses Dietary and Leptin-Deficient Diabetes Endocrinology, June 1, 2004; 145(6): 2594 - 2603. [Abstract] [Full Text] [PDF]
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 C. Yu, F. Wang, C. Jin, X. Huang, D. L. Miller, C. Basilico, and W. L. McKeehan Role of Fibroblast Growth Factor Type 1 and 2 in Carbon Tetrachloride-Induced Hepatic Injury and Fibrogenesis Am. J. Pathol., October 1, 2003; 163(4): 1653 - 1662. [Abstract] [Full Text] [PDF]
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J. A. Holt, G. Luo, A. N. Billin, J. Bisi, Y. Y. McNeill, K. F. Kozarsky, M. Donahee, D. Y. Wang, T. A. Mansfield, S. A. Kliewer, et al. Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis Genes & Dev., July 1, 2003; 17(13): 1581 - 1591. [Abstract] [Full Text] [PDF]
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, Control; 
, transgenic. For A–C, *, P < 0.05; #, P < 0.01.
, CPTI, citrate lyase (CL), and ACC2 in the livers of transgenic mice and the appropriate control mice. B, Triglyceride levels in the liver and muscle of mice fed either of a low fat (LF) or high fat (HF) diet. 
