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. 2014 Oct 7;20(4):670-7.
doi: 10.1016/j.cmet.2014.07.012. Epub 2014 Aug 14.

FGF21 acts centrally to induce sympathetic nerve activity, energy expenditure, and weight loss

Bryn M Owen  1 , Xunshan Ding  2 , Donald A Morgan  3 , Katie Colbert Coate  4 , Angie L Bookout  1 , Kamal Rahmouni  3 , Steven A Kliewer  5 , David J Mangelsdorf  6
Affiliations

FGF21 acts centrally to induce sympathetic nerve activity, energy expenditure, and weight loss

Bryn M Owen et al. Cell Metab. .

Abstract

The mechanism by which pharmacologic administration of the hormone FGF21 increases energy expenditure to cause weight loss in obese animals is unknown. Here we report that FGF21 acts centrally to exert its effects on energy expenditure and body weight in obese mice. Using tissue-specific knockout mice, we show that βKlotho, the obligate coreceptor for FGF21, is required in the nervous system for these effects. FGF21 stimulates sympathetic nerve activity to brown adipose tissue through a mechanism that depends on the neuropeptide corticotropin-releasing factor. Our findings provide an unexpected mechanistic explanation for the strong pharmacologic effects of FGF21 on energy expenditure and weight loss in obese animals.

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Figures

Figure 1
Figure 1. Klb expression in the nervous system is required for the effects of FGF21 on whole body energy expenditure
(A) Body weight in chow-fed groups of Klbfl/fl, Klbfl/fl/Tg, KlbCamk2a and KlbCamk2a/Tg mice. (B) Percent change in body weight in groups of mice fed a high fat diet (HFD). Body weights for the groups at the end of the study were (in grams): Klbfl/fl, 44±2.5; Klbfl/fl/Tg, 33±1.7; KlbCamk2a, 40±1.3; KlbCamk2a/Tg, 47±2.6. (C) Body composition after 8 weeks on HFD. (D) 24-hour food consumption (normalized to body weight) and physical activity on a HFD. (E) Left panel, energy expenditure starting 24 hours after switching mice to the HFD. Right panel, quantification of 24-hour energy expenditure data for the same mice on either regular chow or HFD. (A-C) were performed with mice housed at 22°-23°. (D, E) were performed using metabolic cages maintained at 21°-22°. Data are shown as the mean ± S.E.M. n=8-13/group (A-C), n=6/group (D and E). *p<0.05 compared to control.
Figure 2
Figure 2. Klb expression in the nervous system is required for the effects of FGF21 on gene expression in high fat diet-fed mice
(A-D) Gene expression was analysed by QPCR in (A) brown adipose tissue (BAT), (B) subcutaneous (sc) white adipose tissue (WAT), (C) epididymal (e) WAT, and (D) liver of Klbfl/fl, Klbfl/fl/Tg, KlbCamk2a and KlbCamk2a/Tg mice after 3 months on the high fat diet. QPCR cycle time values are shown for the group with highest expression for each gene. Data are shown as the mean ± S.E.M. n=8-13/group. *p<0.05 compared to control.
Figure 3
Figure 3. Klb expression in the nervous system is required for metabolic actions of recombinant FGF21 delivered by minipump
(A, B) Groups of diet-induced obese mice were administered FGF21 (0.8 mg/kg/day) or vehicle by osmotic minipump for 2 weeks and evaluated for (A) percent change in body weight (day 1 vs day 14), body composition and plasma insulin, glucose, cholesterol and leptin concentrations (day 14) or (B) uncoupling protein-1 (Ucp1) gene expression in brown adipose tissue (BAT) and subcutaneous white adipose tissue (scWAT). For (A), body weights for the groups at the end of the study were (in grams): Klbfl/fl/vehicle, 34±1.3; Klbfl/fl/FGF21, 30±1.0; KlbCamk2a/vehicle, 36±1.6; KlbCamk2a/FGF21, 36±1.3. Data are shown as the mean ± S.E.M. n=5-6/group. *p<0.05 compared to vehicle.
Figure 4
Figure 4. FGF21 acts centrally to stimulate brown adipose tissue sympathetic nerve activity
(A) epresentative sympathetic nerve activity (SNA) recordings at baseline and 4 hours after intracerebroventricular (icv) administration of FGF21 (1 μg) or vehicle. (B) Left panel, percent change in BAT SNA following icv injection of FGF21 (1 μg) or vehicle. Right panel, percent change in BAT SNA at 4 hours following icv injection of FGF21 at the indicated doses. Mice were pre-treated for 10 minutes with either vehicle or an FGF receptor inhibitor (PD173074, 25 μg) delivered icv as indicated. (C) Left panel, percent change in BAT SNA following intravenous (iv) injection of vehicle (V) or FGF21 (1 mg/kg). Right panel, percent change in BAT SNA at 4 hours following iv injection of FGF21. Mice were pre-treated for 10 minutes with either PD173074 or vehicle delivered icv as indicated. (D) Left panel, percent change in BAT SNA following iv injection of FGF21 (1 mg/kg) into Klbfl/fl or KlbCamk2a mice. Right panel, quantification of SNA data at the 4-hour time point. (E) Crf mRNA levels in whole hypothalamus and plasma adrenocorticotropic hormone (ACTH) concentrations 3 hours after ip injection with either vehicle or FGF21 (1 mg/kg). (F) Percent change in BAT SNA 4 hours after icv injection of FGF21 (1 μg). Mice were pre-treated for 10 minutes with either vehicle (saline, 2 μl) or α-helical CRF(9-41) (αhCRF(9-41); 6 μg) delivered icv as indicated. Data are shown as the mean ± S.E.M. n=5-7/group. *p<0.05 compared to either vehicle (B,C,E) or Klbfl/fl (D) as determined by t-test. For (B-D, right hand panels) and (F), the percent change in BAT SNA was calculated based on the average of the final four time points relative to baseline. (G) odel for the effects of FGF21 on energy expenditure. FGF21 acts on the hypothalamus to induce corticotropin-releasing factor (CRF) and to stimulate sympathetic nerve activity (SNA), which in turn induces uncoupling protein 1 (UCP1) and lipolysis in brown adipose tissue (BAT). FGF21 also acts directly on BAT to stimulate glucose uptake and to mobilize oxidative substrate. These dual effects induce efficient energy expenditure. The model is based on this study and previous literature (Cannon and Nedergaard, 2004; Ding et al., 2012).
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References

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