ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Nat Metab 2019;1:1202–1208.

Metformin has become a mainstay in the treatment of T2DM in over six decades of clinical use and is today one of the world’s most commonly prescribed drugs. Anti-diabetic properties of metformin rely on an inhibition of hepatic glucose output through AMPK-dependent, but also AMPK-independent effects (reviewed in (1)). Nevertheless, proposed mechanisms explaining the glucose-lowering, insulin-sensitizing actions of metformin do not explain its moderate weight loss effects (2). Recent observational data identified growth differentiation factor 15 (GDF15) as a novel biomarker for metformin treatment, with GDF15 levels reflecting the dose of metformin in T2DM adults participating in the ORIGIN trial (3). GDF15 is a peptide hormone produced as part of the organism’s stress response, and levels increase after exercise, and tissue injury (4, 5). GDF15 levels are also elevated in obese subjects (6) and seem to persistently increase following bariatric surgery, correlating with weight loss achieved by this surgical intervention (7). In rodents, GDF15 exerts its anorectic effects through the GDNF family receptor α-like (GFRAL) complex, which is solely expressed in the hindbrain (6).

Here, Day et al. hypothesized that metformin decreases body weight by inducing secretion of a hepatocyte-derived endocrine factor that communicates with the CNS. Unbiased transcriptomics of metformin-stimulated mouse hepatocytes and of serum proteomes from patients with T2DM treated with metformin revealed that, of the upregulated gene products in mouse hepatocytes, the most significantly upregulated corresponding protein in human serum was GDF15. Further experiments in cultured primary mouse hepatocytes demonstrated that metformin increased GDF15 expression by 55% and GDF15 secretion in a dose-dependent manner, independent of the AMPK pathway, and through stress response pathways involving ATF4 and CHOP. Next, the authors generated GDF15-knock out mice and assessed the effects of metformin on energy homeostasis in these animals compared to wildtype mice. In wildtype animals, metformin not only increased serum GDF15 and improved glucose tolerance, but also reduced food intake and weight gain under conditions of a high fat-diet (HFD). These metabolically beneficial effects were absent in GDF15-KO-mice on a HFD, but similar to wildtype animals when chow-fed. This finding points to a diet-specific effect of GDF15-induced suppression of food-intake. Interestingly, there were no differences in physical activity and energy expenditure between wildtype and knock out-animals.

Further support for these exciting findings comes from another very recent publication by Coll et al. (8). These authors demonstrate in their own series of experiments that in wildtype mice serum GDF15 levels are increased by oral metformin through increased GDF15 expression in the intestine and kidneys. As in Day et al., Coll et al. report that metformin ameliorated weight gain on high fat-diets in wildtype mice, but not in GDF15-KO mice or in mice lacking the GDF15-receptor GFRAL. Treatment with a GFRAL-antagonist antibody also reversed the weight-lowering effects of metformin in obese mice.

Taken together, these results confirm the need for intact GDF15-GFRAL-signaling for metformin-induced weight loss. As GDF15-mediated weight loss seems to be independent of leptin and GLP-1 signaling, as observed in respective mouse loss-of-function models (6), the recent studies by both Day et al. and Coll et al. open up interesting and new perspectives on the use of metformin to promote weight loss and as a potential cornerstone of future combination therapy regimens, e.g. together with GLP-1 agonists and other weight loss-drugs.

References:

1. Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetologia 2017;60:1577–1585.

2. Apolzan JW, Venditti EM, Edelstein SL, Knowler WC, Dabelea D, Boyko EJ, Pi-Sunyer X, Kalyan RR, Franks PW, Srikanthan P, Gadde KM, PPRG Diabetes. Long-Term Weight Loss With Metformin or Lifestyle Intervention in the Diabetes Prevention Program Outcomes Study. Ann Intern Med 2019;170:682–690.

3. Gerstein HC, Pare G, Hess S, Ford RJ, Sjaarda J, Raman K, McQueen M, Lee S, Haenel H, Steinberg GR, I ORIGIN. Growth Differentiation Factor 15 as a Novel Biomarker for Metformin. Diabetes Care 2017;40:280–283.

4. Kleinert M, Clemmensen C, Sjøberg KA, Carl CS, Jeppesen JF, Wojtaszewski JFP, Kiens B, Richter EA. Exercise increases circulating GDF15 in humans. Mol Metab 2018;9:187–191.

5. Tsai VWW, Husaini Y, Sainsbury A, Brown DA, Breit SN. The MIC-1/GDF15-GFRAL Pathway in Energy Homeostasis: Implications for Obesity, Cachexia, and Other Associated Diseases. Cell Metab 2018;28:353–368.

6. Mullican SE, Rangwala SM. Uniting GDF15 and GFRAL: Therapeutic Opportunities in Obesity and Beyond. Trends Endocrinol Metab 2018;29:560–570.

7. Kleinert M, Bojsen-Møller KN, Jørgensen NB, Svane MS, Martinussen C, Kiens B, Wojtaszewski JFP, Madsbad S, Richter EA, Clemmensen C. Effect of bariatric surgery on plasma GDF15 in humans. Am J Physiol Endocrinol Metab 2019;316:E615-E621.

8. Coll AP, Chen M, Taskar P, Rimmington D, Patel S, Tadross JA, Cimino I, Yang M, Welsh P, Virtue S, Goldspink DA, Miedzybrodzka EL, Konopka AR, Esponda RR, Huang JT, Tung YCL, Rodriguez-Cuenca S, Tomaz RA, Harding HP, Melvin A, Yeo GSH, Preiss D, Vidal-Puig A, Vallier L, Nair KS, Wareham NJ, Ron D, Gribble FM, Reimann F, Sattar N, Savage DB, Allan BB, O’Rahilly S. GDF15 mediates the effects of metformin on body weight and energy balance. Nature 2020;578:444–448.