Effects of metformin on weight loss

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Purpose of review. Despite the known glucose-lowering effects of metformin, more recent clinical interest lies in its potential as a weight loss drug. Herein, we ...
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Effects of metformin on weight loss ARTICLE in CURRENT OPINION IN ENDOCRINOLOGY DIABETES AND OBESITY · AUGUST 2014 Impact Factor: 3.37 · DOI: 10.1097/MED.0000000000000095 · Source: PubMed

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Sangeeta R Kashyap

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Cleveland Clinic

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REVIEW URRENT C OPINION

Effects of metformin on weight loss: potential mechanisms Steven K. Malin a and Sangeeta R. Kashyap b

Purpose of review Despite the known glucose-lowering effects of metformin, more recent clinical interest lies in its potential as a weight loss drug. Herein, we discuss the potential mechanisms by which metformin decreases appetite and opposes unfavorable fat storage in peripheral tissues. Recent findings Many individuals struggle to maintain clinically relevant weight loss from lifestyle and bariatric surgery interventions. Long-term follow-up from the Diabetes Prevention Program demonstrates that metformin produces durable weight loss, and decreased food intake by metformin is the primary weight loss mechanism. Although the effect of metformin on appetite is likely to be multifactorial, changes in hypothalamic physiology, including leptin and insulin sensitivity, have been documented. In addition, novel work in obesity highlights the gastrointestinal physiology and circadian rhythm changes by metformin as not only affecting food intake, but also the regulation of fat oxidation and storage in liver, skeletal muscle, and adipose tissue. Summary Metformin induces modest weight loss in overweight and obese individuals at risk for diabetes. A more detailed understanding of how metformin induces weight loss will likely lead to optimal co-prescription of lifestyle modification with pharmacology for the treatment of obesity independent of diabetes. Keywords appetite, GLP-1, hypothalamus, obesity, type 2 diabetes

INTRODUCTION Approximately 78 million adults and 12.5 million children and adolescents are obese in the USA [1]. Obesity is a major public health concern because it is responsible for more than 2.8 million deaths worldwide per year, owing to an increased prevalence of cardiovascular disease (CVD), cancer, and type 2 diabetes [2]. Despite the randomized clinical trials (RCTs) showing efficacy for lifestyle modification on weight loss, long-term adherence to diet and exercise remains difficult and people oftentimes require pharmacological therapy to manage body weight and metabolic health. Metformin (i.e. 1,1-dimethyl-biguanide) is the first-line, oral, glucose-lowering medication recommended by the American Diabetes Association for people with type 2 diabetes and individuals with prediabetes and at least one CVD risk factor (e.g. hypertension, dyslipidemia, etc.) [3,4]. The mechanism(s) by which metformin improves glycemic control involves reducing hepatic glucose production, enhancing peripheral insulin sensitivity,

and blocking gastrointestinal glucose absorption [3]. Although weight loss is often reported as a favorable ‘side-effect’ of metformin, there are few data showing weight loss in nondiabetic patients. Here, we summarize the progress over the last 3 years, emphasizing studies relevant to metformin as an antiobesity therapy in nondiabetic patients. We present evidence suggesting that metformin reduces weight through appetite regulatory pathways in the brain, with additional influences on adipose and gut-derived signals (Fig. 1). The present review also highlights the recent work describing a Department of Pathobiology, Lerner Research Institute, Cleveland Clinic and bDepartment of Endocrinology, Diabetes and Metabolism, Cleveland Clinic, Cleveland, Ohio, USA

Correspondence to Sangeeta R. Kashyap, MD, Department of Endocrinology, Diabetes and Metabolism, Cleveland Clinic, 9500 Euclid Avenue (NE40), Cleveland, OH 44195, USA. Tel: +1 216 444 2679; fax: +1 216 445 1656; e-mail: [email protected] Curr Opin Endocrinol Diabetes Obes 2014, 21:323–329 DOI:10.1097/MED.0000000000000095

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KEY POINTS  Metformin is an oral pharmacological agent that not only reduces type 2 diabetes and cardiovascular risk, but also produces modest and durable weight loss.  Metformin causes weight loss by reducing food intake. Metformin primarily acts on the central nervous system to reduce appetite by attenuating hypothalamic AMPK activity, which decreases NPY (orexigenic) and increases POMC (anorectic) expression.  Metformin has additional food-lowering effects by improving leptin and insulin sensitivity, increasing GLP-1 levels, and affecting gut flora. Metformin also reduces ectopic lipid depots (i.e. liver and skeletal muscle) through increased fat oxidation and decreased lipid synthesis, which may be regulated to some extent by circadian clock genes.  The interaction of metformin with lifestyle modification and secondary antidiabetic pharmacological agents remains understudied, although a few studies suggest enhanced weight loss by combining treatments with metformin in people at risk for type 2 diabetes. Understanding the metformin-induced weight loss mechanisms of action may lead to optimal treatment strategies that prevent or reverse type 2 diabetes and obesity itself.

the effects of metformin on the interaction of fat metabolism and circadian clock genes. Lastly, we discuss the clinical relevance of combining metformin with exercise and other diabetic and antiobesity medications for obesity-related comorbidities.

IS METFORMIN A VIABLE ANTIOBESITY DRUG? Given the consistent weight loss following metformin administration in type 2 diabetic patients [5], there has been interest in determining the efficacy of metformin as an antiobesity agent in nondiabetic patients. To date, the best study of metformin on body weight comes from the Diabetes Prevention Program [6]. Within the first 3 years of this doubleblind RCT, metformin treatment of 1700 mg/day induced weight loss of approximately 2.9 vs. 0.42 kg in the control group. Impressively, this weight loss effect persisted up to 8 years. These findings are consistent with the shorter trials in individuals with upper body obesity and metabolic syndrome or normoglycemic individuals with a BMI greater than 27 kg/m2, whereby metformin treatment of 1700–2500 mg/day promoted 2–5 kg weight loss up to 1 year [7,8 ]. Recently, Malin et al. [9] demonstrated that 2000 mg/day of metformin for 3 months induced approximately 3 kg &

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weight loss in obese adults with prediabetes, with or without exercise, compared with placebo or exercise training alone. Metformin administered at 2000 mg/day was also reported to induce greater weight loss in obese insulin-resistant adolescents during a lifestyle intervention compared with metformin alone, suggesting that metformin has additive anorectic effects to exercise [10]. To date, however, the optimal diet therapy to be combined with metformin has received little attention [11], and this is important as high glycemic carbohydrates may exacerbate gastrointestinal distress by metformin. Further work in this area is needed given that low carbohydrate diets induce greater weight loss but are often unsustainable over the long term than low-fat diets. Nonetheless, recent work indicates that metformin at lower doses of 1000–1500 mg/day is a viable antiobesity agent in individuals with psychiatric disorders [12] and polycystic ovarian syndrome [13] that are associated with insulin resistance and weight gain, supporting the notion that metformin is a credible weight loss drug in nondiabetic patients.

POTENTIAL WEIGHT LOSS MECHANISMS BY METFORMIN Metformin promotes weight loss by reducing food intake, as changes in total daily energy expenditure are not evident [5,9,14,15]. Interestingly, decreases in meal size are noticed during initial metformin treatment, whereas reductions in meal number continue over time [16 ]. These observations of meal patterns are important because it provides insight into the potential brain regions affected by metformin. &&

Central nervous system regulation The hypothalamus is richly innervated by neurons that regulate feeding and metformin may directly affect the feeding behavior. Diabetic rats administered oral metformin were reported to have elevated concentrations of the drug in the cerebrospinal fluid, suggesting that metformin can cross the blood–brain barrier to affect the hypothalamus [17]. Indeed, metformin reduces food intake by decreasing the orexigenic peptides, neuropeptideY (NPY), and agouti-related protein (AgRP) in the hypothalamus. As metformin regulates the interaction of insulin resistance and adenosine monophosphate-activated kinase (AMPK) in the liver, skeletal muscle, and adipose tissue, it would seem reasonable that metformin mediates anorectic effects by altering hypothalamic AMPK. In response to low blood glucose or caloric deficit, ghrelin is an Volume 21  Number 5  October 2014

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Metformin and weight loss Malin and Kashyap

Food intake NPY and AgRP POMC Leptin and insulin sensitivity

AMPK

Insulin-stimulated glucose uptake

Rx

Metformin

AMPK

Fat oxidation

CHO absorption GLP-1 Gut flora

AMPK

AMPK

Leptin Weight

Hepatic glucose production Fat synthesis Cholesterol synthesis

FIGURE 1. Potential weight loss mechanisms following metformin treatment in brain, skeletal muscle, gastrointestinal tract, adipose tissue, and liver. Metformin has tissue-specific effects on AMPK that collectively favors reduced food intake through neuronal and endocrine related mechanisms. In addition, metformin increases fat oxidation and decreases ectopic lipid stores thereby complimenting the overall reductions in body weight. AgRP, agouti-related protein; AMPK, adenosine monophosphate kinase; CHO, carbohydrate; GLP-1, glucose-like polypeptide-1; NPY, neuropeptide-Y; POMC, pro-opiomelanocortin; D, change in gut microbiota community.

orexigenic hormone secreted from the stomach that stimulates eating by increasing NPY and AgRP neural activity via AMPK. As metformin lowers blood glucose and body weight, it is not surprising that some reports indicate higher ghrelin levels in humans with type 2 diabetes. This apparent discrepancy between weight loss and elevated ghrelin is likely explained by the fact that centrally administered metformin in rodents blocks ghrelin-induced activation of AMPK [18]. Although these findings are consistent with the studies indicating that metformin blocks hypoglycemia-induced AMPK activation in rat primary hypothalamic neurons, others have not observed reduced AMPK activity with metformin under normal glucose concentrations, suggesting that metformin has unique effects on hypothalamic AMPK based on the metabolic milieu [19]. In either case, signal transducer and activator of transcription 3 (STAT3) was recently identified as a key mediator of feeding, and STAT3 activation is associated with the leptin receptor. Metformin increases STAT3 signaling in the hypothalamus and inhibits NPY and AgRP expression [17,19], highlighting that metformin regulates food intake by affecting multiple appetite regulatory pathways.

Another potential factor affecting food intake by metformin is related to the nonspecific toxic mechanisms that induce gastrointestinal stress (e.g. nausea, diarrhea, etc.) and taste disturbances. The nucleus tractus solitarius (NTS) is embedded in the medulla oblongata and important for feeding behavior because this is the first synaptic contact for vagal afferent projections from the gastrointestinal tract. The hindbrain also contains the area postrema, where the blood–brain barrier is circumvented, and accessible to feeding signals through both vagal afferents and circulating hormones [e.g. leptin, insulin, glucagon-like peptide-1 (GLP-1), etc.]. In addition, the NTS and area postrema are important neurocircuits that innervate multiple forebrain regions, including the hypothalamus, to modulate energy status. The role of metformin on meal intake via changes in NTS and area postrema activity has received less attention compared to that of the hypothalamus, but recent work demonstrates that metformin increases c-FOS expression in the NTS, a marker of neural activation, and parallels reduced meal intake [16 ]. &&

Adiposity sensors Because metformin reduces fat mass, it is worth considering that metformin directly affects the

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signaling mechanisms between the adipose–brain axis to regulate food intake. Leptin is an important adipocyte-derived hormone that regulates energy balance and counteracts the influence of ghrelin. Although leptin directly binds to obesity receptor b, which is located mainly in the hypothalamus to increase energy expenditure, leptin also inhibits hypothalamic AMPK activity to suppress NPY and AgRP expression [20]. Additionally, leptin activates STAT3 in the NTS, which contributes to the anorectic effects in the hypothalamus. Metformin improves leptin sensitivity, as reflected by lower circulating leptin levels and elevated leptin receptor expression, and subsequently reduces AMPK activity in the hypothalamus [21]. Moreover, rodent work indicates that metformin increases mamalian target of rapamycin, a downstream target of AMPK that mediates the effects of leptin, and suppresses appetite [18]. Although satiation by metformin may be more prominent in obese models with hyperleptinemia compared with lean controls [22], metformin reduces leptin secretion per se prior to weight loss [23]. Together, these findings suggest that adipose signals monitoring body fat over the long term likely act as secondary messengers influencing food intake by metformin. Insulin sensitivity rises after metformin treatment, and insulin acts as an important energy status signal regulating adiposity. This notion is somewhat counter-intuitive because hyperinsulinemia can lead to a drop in blood glucose that in turn stimulates compensatory neuronal pathways to increase eating and decrease satiety. In addition, insulin is mostly recognized as an anabolic hormone stimulating fat storage in peripheral tissues. However, insulin binds to its receptors in the hypothalamus and suppresses AMPK, thereby mimicking much of the anorectic effects of leptin [20]. Moreover, obesity is associated with insulin resistance in the brain, which contributes to higher AMPK activity and decreased pro-opiomelanocortin (POMC) in the hypothalamus [24]. Thus, reducing insulin resistance may contribute to improved appetite regulation by not only improving glucose-specific changes in appetite regulation, but also enhancing anorectic signaling pathways in the hypothalamus to reduce food cravings. Given that metformin increases leptin hypothalamic sensitivity and whole-body insulin sensitivity by 20–30% [21], it reasons that metformin may accentuate other signals [e.g. GLP-1, peptide tyrosine tyrosine (PYY), cholecystokinin (CCK), among others] that regulate food intake in the brain.

Gut-mediated signals inducing satiety Metformin induces weight loss by enhancing satiation signals secreted by the gut. GLP-1 is a hormone 326

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produced in the L-cell of the gastrointestinal tract in response to nutrient intake, with secondary production in the NTS cell bodies of the brain stem [25]. GLP-1 reduces appetite by acting on vagal afferents that reach the NTS and by directly decreasing hypothalamic AMPK activity, which is associated with elevated POMC [26]. Elevated GLP-1 in turn slows gastric motility and emptying in individuals and contributes to reduced carbohydrate absorption and circulating glucose. Importantly, when midbrain transected rats are studied to investigate the neural pathway from the hindbrain to the hypothalamus, it was demonstrated that the NTS alone has less prominent effects of reducing food intake by GLP-1 and leptin [27]. These findings imply that both circulating and neural factors are likely to be involved in the regulation of food intake. Metformin potentially reduces hunger and affects carbohydrate absorption by raising GLP-1 either through inhibiting dipeptidyl peptidase-IV (DPP-IV), which is an important enzyme for degrading GLP-1 [28], and altering muscarinic and gastrin-releasing peptide related pathways [29]. This elevated GLP-1 may also be influenced by metformin-induced changes in the gut microbiota [30 ], which have been strongly implicated in energy extraction, obesity, and diabetes. In fact, recent work demonstrates that metformin directly affects the enterocyte by not only increasing glucose utilization in the intestinal mucosa [31], but also altering immune signals derived from the gut in rodents that regulate energy homeostasis and insulin action [30 ]. Thus, as PYY and CCK are not directly affected by metformin, higher GLP-1 in humans, and likely changes in gut flora, appears to be an enteroendocrine mechanism influencing body weight. Indeed, when metformin is co-prescribed with DPP-IV inhibitors or exenatide (a GLP-1 receptor agonist), greater weight loss and glycemic control compared with metformin alone is observed in rodents and adults with type 2 diabetes [32]. &&

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ACTION OF METFORMIN TO INCREASE FAT METABOLISM In addition to whole-body weight loss, metformin induces favorable changes on fat metabolism. In fact, metformin not only lowers circulating lipids, but also decreases the concentration of hepatic lipids. Reduced hepatic steatosis following metformin treatment is consistent with the AMPK-mediated increase in fat oxidation and decrease in lipogenesis [33 ]. Indeed, AMPK activation stimulates acetyl-CoA carboxylase (ACC) phosphorylation, which in turn decreases malonyl-CoA concentrations and increases carnitine palmitoyltransferase-1 activity for the &

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promotion of mitochondrial fat oxidation. In addition, AMPK inhibits lipogenic gene expression of fatty acid synthase, 3-hydroxy-3-methylgutarylCoA reductase, and ACC in the liver to decrease lipid storage. Recently, Kim et al. [34] reported that thyroid hormone receptor 4 was also inactivated by metformin in an AMPK-related manner that led to reduced stearoyl-CoA desaturase 1 (SCD1) expression, which is important for the biosynthesis of monounsaturated species of ceramide and diacylglycerol from saturated fatty acids. Decreased SCD1 resulted in reduced fat mass and increased insulin sensitivity with elevated lipid oxidation and decreased lipogenesis. Interestingly, exercise may influence the effect of metformin on fat metabolism, as recent work suggested that metformin attenuates improvements in glycemic control, liver diacylglycerol content, and measures of de novo lipogenesis following exercise in rodents [35 ]. Although further work investigating the interaction of metformin and exercise is needed, the literature suggests that metformin favorably affects hepatic fat metabolism. Skeletal muscle is the chief tissue responsible for insulin-stimulated glucose uptake, and AMPK is a key enzyme regulating energy metabolism [36]. In fact, metformin increases skeletal muscle AMPK activity, which is important for increasing hexokinase II, GLUT-4 transporters, and mitochondrial biogenesis. These favorable skeletal muscle characteristics are consistent with increased energy supplies of intramuscular triglycerides (IMTGs) stores in physically active individuals. Exercise is well known to increase reliance on fat compared with rest, and a primary mechanism for this upregulation in lipid utilization is through skeletal muscle AMPK activity. Recently, metformin administration for 7–10 days increased lipid oxidation across a range of exercise intensities in overweight but healthy individuals [37], suggesting that metformin may augment fat utilization in skeletal muscle. However, the chronic effect of metformin on exercise training fuel adaptations is unclear, as metformin partially inhibited cardiorespiratory fitness and fat oxidation gains in adults with prediabetes [38 ]. Thus, consistent with the work in the liver [35 ], further studies are needed to understand the molecular interaction of metformin with exercise on skeletal muscle to optimize the strategies that prevent diabetes. Nevertheless, the current literature highlights metformin as a potential modifier of fat metabolism in skeletal muscle, as metformin reduces IMTG in adults with type 2 diabetes [39], possibly by reducing ceramide and diacylglycerol species through downregulation of FAT/CD36 transporters [40]. &

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EFFECT OF METFORMIN ON CIRCADIAN RHYTHM Food intake is influenced by homeostatic mechanisms related to meal size, whereas meal number is thought to be under the control of environmental factors including convenience, social gatherings, and diurnal rhythms. Indeed, feeding behavior is influenced by the circadian system composed of a central clock in the brain [41 ] and oscillators in peripheral tissues [42]. Interestingly, circadian rhythm has been implicated in the development of obesity and type 2 diabetes. In obese db/db mice and high-fat fed mice, metformin increased the expression of adipose-derived circadian locomotor output cycles kaput (CLOCK), brain and muscle aryl hydrocarbon receptor nuclear translocator-line 1 (BMAL1), and period (PER) 2 through AMPK activation, which were paralleled by improvements in insulin sensitivity and glycemic control [43]. Moreover, Barnea et al. [44] demonstrated that metformin increased leptin levels, while inducing AMPK activity in both skeletal muscle and liver. These peripheral findings were linked with activation of liver casein kinase 1-a and skeletal muscle casein kinase 1-e, suggesting that metformin alters the circadian clock pathways in multiple tissues and contributes to the regulation of energy metabolism. Further work in humans on chronotherapy is needed to understand the implications for obesityrelated disease treatment. &&

CONCLUSION Obesity is integral to the development of type 2 diabetes and CVD. Although lifestyle modification and bariatric surgery leads to successful weight loss, maintenance of this lower weight is difficult because of strong compensatory mechanisms that promote feeding to restore energy balance. Metformin is a viable pharmacological agent for promoting modest weight loss in overweight people with cardiometabolic risk factors through multilevel effects on neuronal appetite pathways and peripheral fat metabolism (Fig. 1). These effects likely explain the effects of metformin to blunt weight gain typically seen with thiazolidinediones, sulfonylureas, or repaglinide. However, although the quantity of weight loss following metformin treatment is clinically relevant for metabolic health, it is minimal (1–5 kg) relative to the amount needed for most overweight and obese people to achieve healthy weight status. Thus, metformin is unlikely to be a sole antiobesity agent for patients needing to lose significant weight (e.g. >25 kg), and metformin should only be considered as an adjunctive therapy to initiate weight loss in obesity-related diseases and

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prevent weight gain because of medication use. In fact, a few preliminary studies suggest that combining metformin with either exercise or other antidiabetic drugs promote greater weight loss, but whether this enhanced weight loss accentuates metabolic health awaits RCTs. The use of metformin in conjunction with other appetite suppressing agents such as phentermine, topiramate, and lorcaserin also seem logical, but clinical efficacy studies on weight loss are lacking. Further work is warranted to elucidate different doses of metformin on the exact appetite mechanism of action as this will help understand how to optimally implement metformin for the prevention and reversal of obesity in addition to type 2 diabetes. Acknowledgements Funding: This study was funded by the American Diabetes Association clinical translational award 1-11-26 CT (to S.R.K.), NIH RO1-DK089547 ( to S.R.K.). S.K.M. wrote the manuscript and S.R.K. reviewed and edited the manuscript. As a result of space limitations, the authors apologize for any article advancing knowledge of weight loss via metformin not included in this review. Conflicts of interest There are no conflicts of interest.

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