Metformin-induced increases in GDF15 are important for suppressing appetite and promoting weight loss

Abstract

Metformin is the most commonly prescribed medication for type 2 diabetes, owing to its glucose-lowering effects, which are mediated through the suppression of hepatic glucose production (reviewed in refs. 1-3). However, in addition to its effects on the liver, metformin reduces appetite and in preclinical models exerts beneficial effects on ageing and a number of diverse diseases (for example, cognitive disorders, cancer, cardiovascular disease) through mechanisms that are not fully understood 1-3. Given the high concentration of metformin in the liver and its many beneficial effects beyond glycemic control, we reasoned that metformin may increase the secretion of a hepatocyte-derived endocrine factor that communicates with the central nervous system 4. Here we show, using unbiased transcriptomics of mouse hepatocytes and analysis of proteins in human serum, that metformin induces expression and secretion of growth differentiating factor 15 (GDF15). In primary mouse hepatocytes, metformin stimulates the secretion of GDF15 by increasing the expression of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP; also known as DDIT3). In wild-type mice fed a high-fat diet, oral administration of metformin increases serum GDF15 and reduces food intake, body mass, fasting insulin and glucose intolerance; these effects are eliminated in GDF15 null mice. An increase in serum GDF15 is also associated with weight loss in patients with type 2 diabetes who take metformin. Although further studies will be required to determine the tissue source(s) of GDF15 produced in response to metformin in vivo, our data indicate that the therapeutic benefits of metformin on appetite, body mass and serum insulin depend on GDF15. Metformin is one of the most widely used medications in the world. It is a strong base that exists in its protonated form at physiological pH and therefore does not pass through cellular membranes easily. In rodents, oral administration of metformin (250-300 mg kg-1 body weight) results in clinically relevant plasma concentrations of approximately 10-15 μM; however, concentrations in the

GDF-15 as a Weight Watcher for Diabetic and Non-Diabetic People Treated With Metformin

“…Similarly, Chung et al (100) showed that induction of GDF-15 upon mitochondrial unfolded protein response (UPR mt ) activation was CHOP-dependent. Interestingly, metformin was reported to increase the expression of ATF4 and CHOP, further stimulating the secretion of GDF-15 in mouse and human hepatocytes (24). Therefore, current evidence indicates that metformin increases GDF-15 gene expression and stimulate GDF-15 secretion by direct induction of integrated stress response regulators ATF4 and CHOP.…”

“…Bodyweight is usually maintained through central nervous system (CNS) circuitry integrating peripheral metabolic feedback signals of either energy surplus or deficit (21,22). Studies have shown converging evidence that growth differentiation factor 15 (GDF-15) mediates metformin's effect on the gut-nervous system axis to decrease body weight (23)(24)(25)(26). GDF-15, a member of the transforming growth factor beta (TGF-b) superfamily, has many names indicating its multiple functions, including macrophage inhibitory cytokine (MIC)-1, non-steroidal antiinflammatory drug-inducible gene (NAG)-1, placental TGF-b (PTGF), prostate-derived factor (PDF), and placental bone morphogenetic protein (PLAB) (27).…”

Growth differentiation factor 15 levels in obese and healthy pregnancies and its relation to insulin resistance and insulin secretory function: a longitudinal study during and after pregnancy

“…We found an inverse correlation between GDF15 increase during pregnancy and FM gain in NW but did not see a relationship between GDF15 and gestational weight gain. Increases in GDF15 mediate adiposity resistance 32 and are linked to reductions in body weight 12,33,34 and in FM 35 . The effect of GDF15 on weight loss is thought to be associated with appetite reduction regulated by binding to the GDNF family receptor α-like (GFRAL) receptor in the hindbrain 32,36 .…”

Pharmacological but not physiological GDF15 suppresses feeding and the motivation to exercise

“…It was recently demonstrated that an increase in circulating GDF15, in response to metformin treatment, promotes weight loss in a GFRAL-dependent fashion 18,19 . Given that prolonged exercise leads to circulating GDF15 levels comparable to the GDF15 levels reported following metformin treatment, it raises the intriguing possibility that exercise-induced increases in endogenous GDF15 mediate the effects of intense exercise on transient food intake suppression 20,21 .…”