GDF15 acts synergistically with liraglutide but is not necessary for the weight loss induced by bariatric surgery in mice

Abstract

Objective Analogues of GDF15 (Growth Differentiation Factor 15) are promising new anti-obesity therapies as pharmacological treatment with GDF15 results in dramatic reductions of food intake and body weight. GDF15 exerts its central anorexic effects by binding to the GFRAL receptor exclusively expressed in the Area Postrema (AP) and the Nucleus of the Solitary Tract (NTS) of the hindbrain. We sought to determine if GDF15 is an indispensable factor for other interventions that cause weight loss and which are also known to act via these hindbrain regions. Methods To explore the role of GDF15 on food choice we performed macronutrient intake studies in mice treated pharmacologically with GDF15 and in mice having either GDF15 or GFRAL deleted. Next we performed vertical sleeve gastrectomy (VSG) surgeries in a cohort of diet-induced obese Gdf15 -null and control mice. To explore the anatomical co-localization of neurons in the hindbrain responding to GLP-1 and/or GDF15 we used GLP-1R reporter mice treated with GDF15, as well as naïve mouse brain and human brain stained by ISH and IHC, respectively, for GLP-1R and GFRAL. Lastly we performed a series of food intake experiments where we treated mice with targeted genetic disruption of either Gdf15 or Gfral with liraglutide; Glp1r -null mice with GDF15; or combined liraglutide and GDF15 treatment in wild-type mice. Results We found that GDF15 treatment significantly lowered the preference for fat intake in mice, whereas no changes in fat intake were observed after genetic deletion of Gdf15 or Gfral . In addition, deletion of Gdf15 did not alter the food intake or bodyweight after sleeve gastrectomy. Lack of GDF15 or GFRAL signaling did not alter the ability of the GLP-1R agonist liraglutide to reduce food intake. Similarly lack of GLP-1R signaling did not reduce GDF15's anorexic effect. Interestingly, there was a significant synergistic effect on weight loss when treating wild-type mice with both GDF15 and liraglutide. Conclusion These data suggest that while GDF15 does not play a role in the potent effects of VSG in mice there seems to be a potential therapeutic benefit of activating GFRAL and GLP-1R systems simultaneously.

GDF15 Induces Anorexia through Nausea and Emesis

“…No increase in c-Fos in the DMV and AP occurred after both GDF15 doses in the shrew. GDF15-induced c-Fos distribution within the dorsal vagal complex in the shrew appears to only partially overlap with observations of GDF15-induced c-Fos in mice (Frikke-Schmidt et al, 2019;Tsai et al, 2014). It is difficult to draw direct comparisons across species with only intuitive assumptions of GFRAL expression or distribution within the shew hindbrain; however, our data in the vomiting shrew may suggest GFRAL to be differentially distributed within the hindbrain in a species-specific manner.…”

“…GDF15 signaling has gained significant attention with the nearly simultaneous recent reporting of the identification and characterization of the GFRAL-RET (GDNF family receptor α-like) receptor complex as the cellular target for GDF15-mediated signaling (Emmerson et al, 2017;Hsu et al, 2017;Mullican et al, 2017;Yang et al, 2017). Since this cluster of findings, numerous reports and reviews have demonstrated promise for GDF15-GFRAL signaling in obesity treatment (Frikke-Schmidt et al, 2019;Patel et al, 2019;Tsai et al, 2018). Recently published data (Hsu et al, 2017) have suggested that GFRAL knockout (KO) mice were insensitive to long-term anorexia and weight loss produced by the highly emetogenic and widely prescribed chemotherapy agent cisplatin (Herrstedt, 2018).…”

The cytokine GDF15 signals through a population of brainstem cholecystokinin neurons to mediate anorectic signalling

“…The GDF15 receptor, GFRAL (GDNF-family receptor α-like) is located exclusively in a small population of cells in the in the area postrema (AP) and nucleus of the tractus solitarius (NTS) of the mouse dorsomedial medulla oblongata, ( Mullican et al, 2017 ; Yang et al, 2017 ; Emmerson et al, 2017 ; Hsu et al, 2017 ) a brainstem region containing a number of characterised neurons that previously have been linked with appetite regulation ( Luckman, 1992 ; Rinaman et al, 1993 ; Larsen et al, 1997 ; Lawrence et al, 2000 ; Luckman and Lawrence, 2003 ; Ellacott et al, 2006 ; D'Agostino et al, 2016 ; Roman et al, 2016 ; Frikke-Schmidt et al, 2019 ). Administration of recombinant GDF15 reduces food intake, but not in GFRAL knock-out mice ( Mullican et al, 2017 ; Yang et al, 2017 ; Emmerson et al, 2017 ; Hsu et al, 2017 ).…”

Fat Mass Regain in Middle-Aged Mice after Sleeve Gastrectomy is divergent from plasma leptin levels

“…An increase in fasting and post-prandial FGF-21 was observed in adolescents up to three months post SG 26 . Additionally, FGF-21 was found to correlate with weight loss in adolescents following SG 27 . We wonder if the lack of an increase in FGF-21 in SG in our study was due to the age of the mice, or whether we missed an early increase in FGF-21 by only testing plasma samples from 2 months after SG.…”