CNS-targeting pharmacological interventions for the metabolic syndrome

The metabolic syndrome (MetS) encompasses medical conditions such as obesity, hyperglycemia, high blood pressure, and dyslipidemia that are major drivers for the ever-increasing prevalence of type 2 diabetes, cardiovascular diseases, and certain types of cancer. At the core of clinical strategies against the MetS is weight loss, induced by bariatric surgery, lifestyle changes based on calorie reduction and exercise, or pharmacology. This Review summarizes the past, current, and future efforts of targeting the MetS by pharmacological agents. Major emphasis is given to drugs that target the CNS as a key denominator for obesity and its comorbid sequelae.

The CNS plays a pivotal role in regulating food intake and energy balance by adjusting daily energy requirements and sustaining bodily functions (8). The CNS receives satiation signals about energy input and availability from the gastrointestinal (GI) tract, as well as adiposity signals about energy storage from the white adipose tissue (WAT). These inputs are integrated in multiple centers within the CNS and incorporated into humoral and neuronal outputs to peripheral effector organs to tightly balance energy, glucose, and lipid metabolism (ref. 9 and Figure 1).

Figure 1

Homeostatic and hedonic control centers in the brain. Drugs targeting control of metabolism by the CNS act mainly via homeostatic and hedonic control centers that govern feeding behaviors, energy and glucose homeostasis, and body weight. The related brain areas are densely interconnected, and receive direct input from circulating nutrients such as glucose or fatty acids, peripheral neuronal networks, and hormonal satiation signals such as GLP-1 or amylin, or hormonal adiposity signals such as leptin. Within the homeostatic and hedonic control centers, the peripheral signals are integrated with sensory input, past experiences, and cues arising from the prevailing stress situation, emotional context, and mood. Ultimately, the signals converge in nuclei such as the hypothalamic paraventricular nucleus and lateral hypothalamus, and induce both adaptations to our ingestive behavior and brain stem–mediated changes to peripheral organ functions and our control of energy and glucose metabolism. AP, area postrema; ARC, arcuate nucleus; FGF21, fibroblast growth factor 21; GI tract, gastrointestinal tract; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1; LH, lateral hypothalamus; NAc, nucleus accumbens; NTS, nucleus of the solitary tract; PVN, paraventricular nucleus; PYY3-36, peptide YY 3-36; VTA, ventral tegmental area.

Homeostatic control centers in the hypothalamus and the brainstem are of particular importance for metabolic control. Both of these brain areas are in close proximity to circumventricular organs (e.g., the median eminence or area postrema) that contain “leaky,” fenestrated capillaries to allow access of peripheral nutrients, metabolites, and hormones. The brainstem integrates short-term satiation signals from the GI tract either directly via the blood, or via input from vagal afferents that innervate the esophagus, stomach, and small intestine. The nerve endings respond to mechanical stimuli such as gastric dilatation, as well as to chemical satiety signals including the postprandially secreted GI hormones cholecystokinin (CCK) (10), glucagon-like peptide-1 (GLP-1) (11, 12), peptide YY (PYY) (13), and apolipoprotein A-IV (ApoAIV) (14). After binding to specific receptors on the vagal afferents, all of these signals converge in the nucleus of the solitary tract in the brainstem and are subsequently relayed to other brain areas to be finally incorporated into output signals to induce satiety.

The hypothalamus, particularly the arcuate nucleus (ARC), provides the pivotal sensing region for adiposity signals including leptin (15) and insulin (16), as well as for glucose. It also receives input from many other parts of the CNS, including the hindbrain. In the ARC, glucoregulatory and glucose-sensing neurons exist alongside two distinct and functionally antagonistic populations of neurons, each characterized by the expression of specific neuropeptides: the anorexigenic proopiomelanocortin-expressing (POMC-expressing) neurons, which are active during a positive energy balance, and orexigenic neurons, which coexpress agouti-related peptide (AgRP) and neuropeptide Y (NPY) and are active during a negative energy balance (17, 18). Neurons within the ventromedial, dorsomedial, and lateral hypothalamus and the paraventricular nucleus play an equally important role in controlling energy and glucose homeostasis. Together, they form a hypothalamic network that integrates with multiple neurocircuits outside of the hypothalamus in order to govern food intake, energy expenditure, glucose metabolism, and insulin sensitivity (18).

Homeostatic signals can be overpowered by nonhomeostatic cues of high hedonic valence (19). For instance, food enriched with fat and sugar can serve as potent reward stimulus. Consequently, highly rewarding food can initiate eating even in the absence of an energetic requirement. Several brain regions and neurotransmitter systems, including dopamine, serotonin, endocannabinoids, and opioids, are involved in the rewarding effect of food (20–23). Also, homeostatic signals such as leptin (24), insulin (25), and ghrelin (26) affect the brain reward system.

Reward in the context of ingestive behavior is built upon two separable functional components: first, the hedonic “liking” of food, which is related to pleasure and palatability and primarily involves the opioid and cannabinoid systems in the nucleus accumbens, ventral pallidum, parabrachial nucleus, and nucleus of the solitary tract; and second, the “wanting” of food, which is related to appetite and the incentive motivation to eat and which is mainly related to the mesolimbic dopaminergic system with its projections from the ventral tegmental area to the nucleus accumbens and neural circuits involving the prefrontal cortex, amygdala, and hypothalamus (27–29).

Small-molecule CNS stimulants have been shown to tackle both components of the food reward system to ultimately suppress appetite. They have thus long been recognized as potential antiobesity drugs, and were the first drugs in use, as outlined below.

In the 1920s, at a time before it was recognized that obesity accounts for a growing prevalence of harmful chronic diseases (30), attitudes concerning body weight began to shift in favor of a slimmer and athletic appearance. The perceptual change boosted the search for pharmacological strategies to facilitate weight loss. The first weight-lowering drugs were identified at a time when the mechanisms for food intake and weight control were largely unknown. Today we know that these appetite suppressants were mainly targeting monoamine neurotransmitter systems, which comprise a network of neurons within homeostatic and hedonic circuits of the brain that use monoamine neurotransmitters including the catecholamines dopamine and norepinephrine and the indolamine serotonin.

Amphetamines, the first monoamine-targeting weight loss drugs. The first monoamine neurotransmitter–based weight loss drug was introduced in the 1930s, when Smith, Kline & French Laboratories synthesized and commercialized the two optical enantiomers of amphetamine: dextroamphetamine and levoamphetamine. Benzedrine contained the racemic mixture of both isomers, while Dexedrine only included the more potent dextroamphetamine. Originally advertised as a treatment for narcolepsy or postencephalitic parkinsonism, the cognitive-enhancing properties of amphetamine were quickly recognized (31). The observation of its potent appetite-suppressing side effect caused an erratic increase in the use of amphetamines as weight loss therapy (31, 32). Therapies arose that combined amphetamine with barbiturates to counter adverse side effects, such as insomnia, restlessness, and increased blood pressure (Dexamyl). Clarkotabs added thermogenic thyroid hormone to enhance weight loss, along with phenobarbital, aloin, and atropine sulfate to reduce undesirable adverse effects. Furthermore, N-methyl–substituted amphetamine (methamphetamine) derivatives, including Desoxyn and Methedrine, were hailed as weight loss drugs (33).

The weight-lowering effect of amphetamine was mainly assigned to a decrease in food intake. When humans were given amphetamine or placebo and required to maintain constant eating, the weight-lowering effect was eradicated (34). Later studies in rodents demonstrated that intraperitoneally injected amphetamine is less effective in suppressing appetite in rats with lateral hypothalamic lesions (35). Moreover, direct hypothalamic injections of amphetamine decreased food intake, and amphetamine action on the lateral hypothalamus was inhibited by local administration of dopaminergic and β-adrenergic antagonists, and by inhibitors of catecholamine synthesis (36). Amphetamine-induced anorexia was linked to a decreased hypothalamic expression of orexigenic NPY (37, 38). Amphetamine therapy was further shown to increase the expression of cocaine- and amphetamine-regulated transcript (CART) (39), a neuropeptide secreted by anorexigenic POMC neurons that decreases food intake (40).

Over time, the widespread consumption of amphetamines displayed a dark side. Multiple users experienced addictive behaviors that went beyond a mere habituation to the effects of amphetamines. This addictive behavior was later assigned to the competitive binding of amphetamine to the norepinephrine transporter (NET) and the dopamine transporter (DAT) (41), which inhibited the reuptake of endogenous norepinephrine and dopamine into the presynaptic neurons. Amphetamines were further shown to promote the reverse transport (efflux) of both monoamines, and to slow catecholamine catabolism by inhibiting monoamine oxidase (ref. 42 and Figure 2). In consequence, amphetamines induced an amplification of the mesolimbic dopaminergic signal transmission in the striatum that profoundly escalated their rewarding and addicting properties (43).

Figure 2

Central monoaminergic drug action. Pharmacological effects of amphetamines and their congeners are primarily mediated by increased synaptic release of monoamine neurotransmitters norepinephrine (NE), dopamine (DA), and, to a lesser extent, serotonin (5-HT). (A) (i) Amphetamines are competitive agonists for NET and DAT. (ii) Upon entering the presynaptic neuron, amphetamines bind to VMAT2, thereby inhibiting monoamine translocation from the cytosolic pool into storage vesicles. (iii) Amphetamines also weakly inhibit monoamine oxidase–mediated (MAO-mediated) monoamine breakdown, resulting in intracellular increase of monoamines. (iv) Amphetamines can further activate the intracellular trace amine-associated receptor 1 (TAAR1) to promote DA efflux. All processes contribute to reverse transport via NET or DAT, enhancing extracellular monoamine release. (v) Elevated monoamine release induces satiety and decreases feeding by activating postsynaptic α- and β-adrenergic (NE) and D1/D2 (DA) receptors. Increased DA signaling within the mesocorticolimbic system contributes to the addictive properties of amphetamines and their congeners. (B) Selective serotonergic drugs act either as (i) serotonin-releasing agents (SRAs), (ii) selective serotonin reuptake inhibitors (SSRIs), or (iii) selective 5-HT2C receptor agonists. SRAs (e.g., fenfluramine) increase synaptic 5-HT release, augmenting serotonergic function. Although SRAs’ precise mechanisms remain unclear, they may be comparable to NE and DA releasers, i.e. reversing SERT- or VMAT2-mediated 5-HT transport. SSRIs (e.g., sibutramine) selectively bind SERT to inhibit 5-HT re-uptake. Postsynaptic 5-HT2C receptors appear to mediate the main effects of 5-HT on food intake and are the target of selective 5-HT2C receptor agonists such as lorcaserin. Presynaptic autoreceptor 5-HT1A and postsynaptic 5-HT1B, 5-HT2B, and 5-HT6 receptors may also contribute to the regulation of food intake by 5-HT. Monoaminergic drugs act at pre- and postsynaptic neurons, and they also interact with monoaminergic signaling on astrocytes. Astrocytic expression of NET, DAT, SERT, and metabolizing enzymes such as MAO can regulate monoamine levels in the synaptic cleft, neurotransmitter release from astrocytes and its transport into presynaptic neurons, and postsynaptic neuron activity.

Past failures and evolution of monoaminergic drugs. The abusive potential of amphetamines prompted the pharmaceutical industry to develop structural derivatives with the goal of decreasing the dopaminergic effect and the risk of habituation (31). Several amphetamine congeners were developed and put into clinical use, some of them with catastrophic results. Aminorex, phenylpropanolamine, and phenmetrazine have been withdrawn from the market because of severe adverse effects (Table 1). At present, four amphetamine congeners — phendimetrazine, diethylpropion, phentermine, and benzphetamine — are approved for the treatment of obesity (Table 2). However, the safety concerns regarding their addictive potential were never fully reconciled. In 1977, all approved amphetamine-derived drugs were restricted to short-term use and were categorized as controlled substances by the US Drug Enforcement Administration (DEA), indicating their respective likelihood for physical addiction and mental dependence. In their capacity as CNS stimulants, their typical unwanted effects include, besides insomnia and nervousness, an increased heart rate. This particular side effect renders them counterindicated for patients with existing cardiovascular problems, including uncontrolled hypertension. Nevertheless, amphetamine congeners, and phentermine in particular, rank as some of the most prescribed antiobesity medications in the United States, either as monotherapy or as combination treatment with the anticonvulsant topiramate (Table 2). In 2017, bupropion, which chemically resembles the amphetamine derivative diethylpropion, was approved for weight loss in combination with the μ/κ-opioid receptor antagonist naltrexone (ref. 44, Table 2, and Figure 3). Phase III clinical trials are currently investigating the weight-lowering effects of bupropion in combination with the anticonvulsant zonisamide (ref. 45 and Table 2).

Figure 3

Drugs targeting the opioid and cannabinoid system. Multiple homeostatic and hedonic control centers of food intake express δ-, κ-, and/or μ-opioid receptors as well as cannabinoid receptor type 1. Endogenous opioids such as enkephalins, endorphins, or dynorphins are important in our response to and moderation of pain and pleasure, and influence both homeostatic and hedonic aspects of eating behavior. Similar actions on food intake are reported for endocannabinoids such as anandamide or 2-arachidonoylglcerol. Accordingly, both systems have been at the focus of the development of antiobesity drugs based on receptor antagonists. To date, only the μ/κ-opioid receptor antagonist naltrexone and the type 1 cannabinoid receptor (CB₁R) antagonist rimonabant have gained market access as weight loss drugs, but psychiatric liabilities led to withdrawal of rimonabant. On presynaptic neurons, both drugs act via inhibition of presynaptic intracellular calcium influx and/or potassium efflux, which ultimately blocks calcium-dependent neurotransmitter vesicle release. Postsynaptically, the antagonist naltrexone inhibits μ- and to a lesser extent κ-opioid signaling to decrease neuronal activity. Rimonabant and naltrexone may further activate astrocyte cannabinoid and opioid signaling to modulate both presynaptic and postsynaptic neuronal processes.

Table 1

Withdrawn monoaminergic antiobesity drugs

Table 2

Monoaminergic antiobesity drugs

To overcome some of the challenges associated with amphetamines mainly acting on dopaminergic and noradrenergic circuitry, novel classes of monoaminergic drugs were developed with a preference for targeting the serotonin system. Serotonin (5-HT) acts as a hormone and a neurotransmitter that regulates a variety of physiological processes in the CNS and in peripheral organs. Serotonin cannot cross the blood-brain barrier, which explains why the peripheral and the central serotonergic systems are functionally separated. In the CNS, serotonin is synthesized and released by serotonergic neurons, which are organized into nine nuclei (B1–B9) and located in the midbrain and hindbrain areas. The most substantial portion of total brain serotonin is synthesized in the dorsal raphe (B7) of the brain stem, which has projections to hypothalamic nuclei and other feeding-related forebrain areas (46). Serotonin acts as a key anorexigenic signal mainly via two distinct types of serotonin receptor–expressing neurons. First, the activation of serotonin 2C receptors (5-HT_2CRs) on POMC neurons (47, 48) leads to an increased release of α-melanocyte-stimulating hormone (α-MSH) and subsequent stimulation of the melanocortin-3 and -4 receptor system (MC3/4Rs) (49). Second, the stimulation of 5-HT_1BRs on NPY and AgRP orexigenic neurons blocks the release of NPY and AgRP and abolishes the inhibitory effect of GABA on POMC neurons (50). In addition, 5-HT₆R antagonists can potently reduce food intake and body weight gain in rodents, but the underlying mechanisms remain to be determined (51). Overall, the serotonin system continues to be a viable target for weight control and has led to the development of three classes of serotonergic drugs: serotonin-releasing agents, serotonin reuptake inhibitors, and selective 5-HT_2CR agonists (Figure 2).

In the 1990s, fenfluramine, a first-generation serotonin-releasing agent, was combined with the sympathomimetic drug phentermine to create the weight-lowering drug Fen-Phen. This combination drug gained great popularity until an increasing number of valvular heart disease and pulmonary hypertension cases were associated with its use (52), ultimately causing the suspension of the combination drug as well as fenfluramine and its derivative dexfenfluramine (Table 1). Similarly, sibutramine, a selective reuptake inhibitor for serotonin and norepinephrine, was withdrawn owing to severe cardiovascular side effects (53) (Table 1). In 1995, the finding that 5-HT_2CRs act as key regulators of satiety in rodents stirred the development of a third generation of serotonergic drugs (54). Lorcaserin is a selective 5-HT_2CR agonist that is thought to decrease food intake through the hypothalamic POMC-melanocortin axis (55) in the absence of serotonergic adverse events (Table 2). Importantly, lorcaserin treatment results in the reduction of multiple cardiovascular risk factors and leads to an improved glycemic control, which renders it applicable for the treatment of the MetS (56). The combined serotonin-noradrenaline-dopamine reuptake inhibitor tesofensine (NS2330) is currently being investigated in phase II clinical trials and may have weight-lowering properties beyond those of existing monoaminergic weight loss medications (Table 2).

Drugs targeting the endocannabinoid system. In the late 1980s, the discovery of type 1 and type 2 cannabinoid receptors (CB₁R and CB₂R) and their endogenous ligands, the endocannabinoids, prompted the development of synthetic receptor agonists and antagonists in order to study the physiological function of the endocannabinoid system (ECS). Major attention has been paid to CB₁R, which is the more abundant CBR in the CNS, particularly the hippocampus, basal ganglia, and hypothalamus (57). CB₁R has also been identified in the GI tract, adipose tissue, skeletal muscle, and cardiovascular system. One of the first described CB₁R inverse agonists (functional antagonist) was SR141716A (rimonabant) (ref. 58 and Figure 3). Chemically, rimonabant is a pyrazole and piperidine derivative, which upon daily i.p. (intraperitoneal) injection caused a profound reduction in body weight and food intake in lean rats (59). This finding was in line with the hypophagic and lean phenotype of mice lacking CB₁R (60). The weight-lowering effect of chronic rimonabant administration was further confirmed in diet-induced obese (DIO) mice (61) and in hyperphagic Lep^ob mice (62). Peripheral CB₁R antagonism was shown to contribute to the weight-lowering effect by enhancing lipolysis in adipocytes (63). The finding of reduced drug-seeking behavior in rimonabant-treated rats (64), and of an attenuated reward behavior in the CB₁R-KO mouse (65), provided strong evidence for the involvement of the ECS in motivation and hedonic behaviors.

Clinical trials confirmed the weight loss efficacy of rimonabant (20 mg) by showing a placebo-subtracted weight loss of 2.6 to 6.3 kg (66, 67). In addition, rimonabant caused a significant improvement in cardiovascular risk factors associated with the MetS (66, 67). In 2009, only three years after rimonabant was introduced to the European market, it was withdrawn based on novel data that linked it with depression and an increased risk for suicide (68). Accumulating evidence suggests that the mood-changing effects were caused by rimonabant’s inverse agonism, which rendered CB₁R in the amygdala and the ventral tegmental area constitutively active (69).

Recently, neutral CB₁R antagonists were developed. They lack the inverse agonist properties of rimonabant and the mood-changing effects, but continue to reduce weight gain and food intake (69). Whether such neutral CB₁R antagonists can represent a novel and safer alternative for the treatment of the MetS remains to be determined. Currently, a novel neutral peripheral cannabinoid antagonist (AM6545) with limited CNS penetration is under investigation (70).

Weight loss drugs that mimic WAT adiposity signals. The increasing understanding of the physiology of food intake and energy balance, and the pathophysiology of its dysregulation, resulted in the development of drugs that interfere with neuropeptide hormone signaling pathways, such as leptin-melanocortin signaling. The adipokine leptin is secreted in direct proportion to fat mass. As an adiposity signal it targets hypothalamic leptin receptors (LepRs) and their downstream JAK2/STAT3, MAPK, and PI3K signaling to decrease food intake and increase energy expenditure in lean individuals. Its main action is driven by LepR-positive AgRP (71, 72) and POMC (73, 74) neurons in the ARC. These first-order neurons sense leptin levels and numerous other hormonal and nutritional cues, and orchestrate the activation of melanocortin-3 and -4 receptor–positive (MC3/4R-positive) neurons in the paraventricular nucleus via direct synaptic innervation or via the concomitant release of the neuropeptide MC3/4R agonist AgRP or the MC3/4R antagonist α-MSH, a cleavage product of POMC (75). The fine-tuning of melanocortin tone by competing neuropeptides ultimately governs ingestive behaviors and behaviors beyond feeding (76–78) as well as non-CNS processes such as thermogenesis and WAT browning (79) or bone metabolism (80).

Subjects with loss-of-function mutations in leptin, LepR, or downstream signaling components such as POMC or MC4R suffer from severe forms of morbid obesity and comorbid sequelae (81). Treatment with recombinant leptin can fully normalize body weight in leptin-deficient patients, but has no beneficial effects in patients with mutations in LepR or its downstream signaling. Currently, only one recombinant leptin analog, metreleptin (Myalepta), is approved for patients with leptin deficiency. The search for downstream mediators of leptin deficiency resulted in the discovery of the orexigenic hypothalamic peptide melanin-concentrating hormone (MCH) (82). Pharmacological blockade of MCH receptor 1 (MCHR1) emerged as promising drug target for the treatment of obesity. However, years of efforts failed to validate the MCHR1 antagonist concept in phase I clinical trials (83).

While monogenetic forms of obesity may often involve mutations in leptin melanocortin signaling, they remain rare and insignificant for the overall majority of obese individuals. These individuals have high leptin levels but exhibit leptin resistance, i.e., a relative inability of endogenous leptin or exogenous recombinant leptin to decrease food intake and body weight. Molecular underpinnings for the insensitivity toward leptin action are not entirely understood and need further investigation. Impaired leptin transport, LepR trafficking, and leptin feedback signaling have been discussed (84), but more recent reports found little evidence for perturbed transport or signaling (85) and suggest fully intact CNS leptin action even in a state of diet-induced obesity (86).

Although leptin resistance remains an enigma, recent results have nonetheless encouraged reconsideration of therapeutic antiobesity strategies built on leptin sensitization. Increasing evidence has demonstrated that leptin sensitivity can be restored by pharmacologically induced weight loss (87–90). Notably, calorie restriction alone was not sufficient to restore leptin sensitivity (89). Pramlintide (Symlin), a synthetic analog of pancreatic amylin, sensitizes mice to the effects of leptin (90). Currently, pramlintide is clinically approved as adjunct therapy to mealtime insulin for the control of blood sugar. The combination of pramlintide with metreleptin resulted in a mean weight loss of 12.7% (90), and future weight loss therapies based on amylinomimetics or combinatorial therapies (e.g., with leptin) appear plausible. In addition, inhibition of the protein tyrosine phosphatase PTP1B, a negative regulator of the leptin and insulin signaling pathway, by trodusquemine (MSI-1436) and related analogs was shown to elicit weight loss and leptin resensitization (91, 92).

Screenings for novel leptin-sensitizing molecules using the bioinformatical Connectivity Map (CMAP) tool led to the identification of the plant constituents celastrol and withaferin A, which increase leptin sensitivity and reduce body weight of obese mice (93, 94). The leptin-sensitizing properties of celastrol were later confirmed (95) and attributed to the hypothalamic inhibition of the protein tyrosine phosphatases PTP1B and TCPTP (96) and to an upregulation of the hypothalamic interleukin-1 receptor 1 (IL1R1) (97).

Restoring leptin sensitivity constitutes a challenge in the field of obesity and offers the unprecedented opportunity to develop an efficient weight loss and weight maintenance therapy. However, clinical data on these novel small-molecule sensitizing drugs are not yet available. They may further be complemented by additional drugs that elicit weight-lowering actions via the leptin-melanocortin system. These drugs include a new generation of small-molecule MC4R agonists such as setmelanotide (RM-493), which has recently been successfully used to treat patients with LepR deficiency (98) or with mutations in POMC (98, 99). Earlier small-molecule MC4R agonists had shown limited weight-lowering efficacy and/or severe cardiovascular liabilities, i.e., increases in blood pressure or heart rate (100, 101). Nonetheless, efforts continue to search for safe yet efficacious MC4R agonists, but their full potential as antiobesity drugs in obese patients remains underexplored.

Weight loss drugs that mimic GI satiety signals. Bariatric surgery is an effective albeit highly invasive option for obese subjects to achieve and sustain long-term weight loss and reductions in all MetS-related symptoms. The finding that bariatric surgery leads to profound changes in the secretion of gut hormones that have effects on food intake and glycemic control provided guidance to the search for new drugs that harness the CNS response to multiple satiety signals from the GI tract.

CCK mainly targets type 1 CCK receptors (CCK1Rs) on vagal afferent neurons to regulate satiety by terminating meals (102). Accordingly, CCK1R agonists were considered as promising antiobesity drugs. However, to date, their therapeutic utility has been limited by compensatory increases in meal frequency (103), by the development of drug tolerance in response to prolonged drug application (104), and by limited weight loss efficacy in phase II clinical trials (105). Additional efforts have been directed toward exploring antiobesity effects of gut-derived PYY3-36. However, discrepant results in rodents (106, 107) and high levels of nausea in humans (108) impeded further clinical developments. PYY3-36 has high affinity for the NPY receptor Y2, which is one of several NPY receptors that play important roles in the regulation of food intake. Major ongoing efforts have been directed toward finding centrally acting agonists or antagonists against Y1, Y2, Y4, or Y5 receptors, but progress to date has been limited (109).

Extensive efforts were directed toward the generation of drugs that mimic the actions of the incretin GLP-1 (Table 3). In the periphery, GLP-1 receptor (GLP-1R) agonists exhibit properties ranging from glucose-dependent stimulation of insulin secretion (110, 111), suppression of glucagon secretion (112), and preservation of β cell mass (113), to the reduction of hepatic glucose output (114), which together leads to improvements in glycemic control. GLP-1R signaling in the brain is crucially involved in the anorectic and weight-lowering effects of GLP-1 (115), which are in part mediated via direct activation of hypothalamic POMC/CART neurons in the ARC (116) or GLP-1R–positive neurons in the nucleus of the solitary tract of the hindbrain (117). Moreover, there is evidence that the inhibitory effect of GLP-1R agonists on food intake goes beyond satiation and includes effects on food reward and motivation (118).

Table 3

Incretin mimetics for the treatment of obesity and type 2 diabetes

Native GLP-1 has a half-life of 2–3 minutes due to rapid degradation by dipeptidyl peptidase-4 (DPP-4), and several GLP-1R agonists have been developed to provide prolonged bioavailability. Depending on their half-life, they can be categorized either as short- or long-acting compounds (Table 3). The short-acting compounds include a synthetic version of exendin-4, exenatide (Byetta), and lixisenatide (Adlyxin). The long-acting compounds include albiglutide (Tanzeum), dulaglutide (Trulicity), exenatide long-acting release (Bydureon), liraglutide (1.8 mg Victoza or 3.0 mg Saxenda), and semaglutide (Ozempic). Differences in the bioavailability of these compounds lead to important differences in their biological actions. Short-acting GLP-1R agonists are applied before a meal and cause a profound deceleration of gastric emptying and a reduction in postprandial glycemia (119, 120). In contrast, long-acting GLP-1R agonists exert stronger effects on fasting glucose levels by causing prolonged stimulation of insulin secretion, but the effects on gastric emptying are subject to rapid tachyphylaxis (121). Consequently, short-acting GLP-1R agonists could be more suitable for the treatment of patients suffering primarily from postprandial hyperglycemia, whereas long-acting GLP-1R agonists would be more suitable for patients with predominant fasting hyperglycemia (122).

Head-to-head comparisons of incretin mimetics so far rendered liraglutide as the most effective antiglycemic GLP-1R agonist (123). The weight-lowering effect of GLP-1R agonists are dose-dependent and are most pronounced for high-dose liraglutide (3 mg) or semaglutide treatment. The latter caused a placebo-subtracted body weight loss of up to 16% in obese patients after 52 weeks of treatment (124), which for the first time comes close to the weight loss achieved by bariatric surgery. Remarkably, an alternative formulation of semaglutide is currently being evaluated as a precedent-setting peptide-based antiobesity/antidiabetes drug that is given by oral administration (125).

The most common adverse effects seen with all GLP-1 therapies include nausea, vomiting, and injection-site reactions. Importantly, GLP-1R agonists do not seem to negatively affect cardiovascular risk in type 2 diabetes (T2D) patients. Novel findings even suggest a cardioprotective action of GLP-1R agonists (126, 127), which may render them as the treatment of choice for MetS patients with cardiovascular symptoms.

A new generation of combinatorial peptide drugs. Structural similarity between GLP-1, glucagon, and the incretin glucose-dependent insulinotropic polypeptide (GIP) and their low-potency cross-reactivity at their respective receptors facilitated integration of each activity into sequence-intermixed unimolecular hybrids. GLP-1 has now been successfully combined with glucagon (128, 129) or GIP into unimolecular dual or tri-agonists (130, 131) in order to achieve synergistic reductions of adiposity and hyperglycemia.

The first GLP-1–based multi-agonist was GLP-1 combined with glucagon action. Apart from its hyperglycemic effect, glucagon is a potent anorectic hormone. It mediates its weight-lowering effect mainly by acting on the CNS as a satiety signal to reduce food intake and by increasing energy expenditure and thermogenesis (132). Accordingly, it was hypothesized that glucagon would increase the weight-lowering effect of GLP-1, while the insulinotropic actions of GLP-1 would counter the hyperglycemic liability of glucagon. A large variety of GLP-1/glucagon receptor coagonists have been developed and advanced to clinical evaluation (133). Two of them, SAR425899 and MEDI0382, were recently shown to induce clinically meaningful reductions in blood glucose and body weight in obese T2D patients (134, 135).

Like GLP-1, the incretin GIP is secreted from the gut in response to nutrient ingestion and promotes insulin secretion in a glucose-dependent manner. While insulinotropic effects of GIP are well defined, controversy exists regarding its weight-lowering potential. Surprisingly, the pharmacological targeting of the GIP receptor (GIPR) by agonists (130, 136–138) as well as by antagonists (139, 140) led to body weight loss in obese rodents. Notably, a recent study aimed at disentangling these contradictory observations by comparing the in vivo potency of several structurally diverse GIPR agonists with a potent long-acting antagonist (138). This study confirmed weight loss in DIO mice only for selective GIPR agonists, but not for the GIPR antagonist. A combination of GLP-1R and GIPR agonism may thus have superior effects on glucose tolerance and body weight loss. Indeed, several studies on GLP-1R/GIPR dual agonists favor beneficial effects of GIP activation in glycemic control in preclinical (130) and clinical trials (141, 142). Tirzepatide (LY3298176), a once-weekly GLP-1/GIP coagonist, was recently shown to be superior to the GLP-1R agonist dulaglutide in terms of body weight loss and improved glycated hemoglobin (HbA1c) in obese human subjects with T2D (142). Whether GIP-based coagonists can provide greater maximal clinical efficacy and fewer side effects compared with the current best-in-class GLP-1R mono-agonist, semaglutide, will require the development of additional coagonist variants and a thorough clinical evaluation.

Based on the promising clinical trials using GLP-1/GIP and GLP-1/glucagon dual agonists, it was predicted that tri-agonist molecules with agonism at all three receptors would provide superior metabolic improvements. Indeed, in DIO mice and obese monkeys, the reduction of body weight by a GLP-1/GIP/glucagon tri-agonist was greater than that by the same dose of a GLP-1/GIP dual agonist (131). The potential benefits of GLP-1/GIP/glucagon tri-agonism for the management of obese individuals with T2D are currently being investigated in clinical trials (133).

The above-described hybrid GLP-1–based multi-agonists are limited to structurally similar molecules. In addition to this approach, fusion peptides have been generated in which structurally diverse hormones or oligonucleotides can be connected to GLP-1 via a chemical linker. GLP-1 fusion molecules with other peptide hormones including gastrin, amylin, and CCK have been generated and shown to achieve enhanced metabolic efficacy (143–145). Finally, there are recently reported successes in developing hybrid drugs that use GLP-1 as a hormonally active peptide for the cell type–specific delivery of chemically conjugated nuclear receptor agonists (146, 147) and antisense oligonucleotides (148). For instance, GLP-1R targeting has been leveraged to deliver estrogen to metabolically relevant tissues, where it enhanced the body weight–lowering, insulinotropic, and islet-preserving effects of estrogen through complementary pharmacology. Importantly, endocrine toxicities in non–GLP-1R–expressing organs were absent, which highlights the cell type–specific delivery (146, 149). In preclinical mouse models, the combination of GLP-1 with the glucocorticoid receptor agonist dexamethasone synergistically drove weight loss, likely mediated by a concomitant decrease in hypothalamic inflammation and GLP-1R–dependent activation of anorexigenic neurons (147). Currently, hybrid drugs are still in preclinical testing, and their clinical safety and efficacy remain to be determined.

Weight reduction plays a fundamental role in managing the MetS. With emerging knowledge about neuronal pathways and peripheral feedback mechanisms controlling hunger and appetite, CNS-targeted weight loss pharmacology continues to evolve toward safer and more efficacious strategies. Currently, targeting strategies are mostly directed toward neuronal networks involved in the regulation of systemic metabolism. Built on the recent observation that systemic metabolism is also functionally controlled by non-neuronal cells in the CNS, including astrocytes, microglia, and tanycytes (150), future targeting strategies may require a wider focus and extraordinary approaches. However, at present it remains largely elusive whether and how disrupted non-neuronal glial networks are functionally involved in the development of the MetS.

Novel therapies may be built on the hormonal signals and CNS pathways discussed above, but they may also use entirely different concepts and strategies. For instance, the past decades saw the discovery of multiple new, hitherto unknown peripheral factors such as meteorin (151), meteorin-like (152), adipsin (153), irisin (154), or GDF15 (155), which have all been linked to energy and glucose homeostasis. These novel factors may hold great promise as backbones for future therapies against the MetS. GDF15 appears to be at center stage in this competitive search for new antiobesity drugs, and has recently been reported as a potent anorexigen that exerts its weight-lowering action via the receptor GDNF family receptor α–like (GFRAL) (156–158). The large family of fibroblast growth factors (FGFs) has gained similar attention in the search for antiobesity and antidiabetes drugs. Secreted by multiple tissues, FGF21 has been shown to exert weight loss and other multisystemic metabolic benefits in rodent models, and several FGF21 mimetics and receptor antagonists have hence entered the clinical testing phase (159). A single dose of FGF1 injected into the hypothalamus was further shown to induce a sustained and full remission of diabetic hyperglycemia in rodents (160, 161), which highlights the potential of FGF-based drugs in the fight against the MetS.

Overall, it is becoming increasingly clear that the complex and individual manifestation of the MetS requires pursuit of tailored therapies that ensure improved efficacy and safety in specific patient cohorts. Such novel therapies further require pioneering new pharmacological concepts and drugs that help close the current therapeutic gap and the relative lack of CNS-driven antiobesity drugs. Lastly, novel therapeutic concepts will greatly benefit from the increasing availability of large data sets and the development of advanced algorithms that facilitate an earlier and individualized patient diagnosis to enrich the prediction of individual risks for the development of comorbidities.

We thank Sandrine Lefort and Cristina García Cáceres for discussion and critical reading of the manuscript. This work was supported in part by funding to MHT from the Alexander von Humboldt Foundation; the Helmholtz Alliance ICEMED; the Helmholtz Initiative on Personalized Medicine (iMed) by the Helmholtz Association; the Helmholtz cross-program topic “Metabolic Dysfunction,” and the Initiative and Networking Fund of the HelmHoltz Association. This work was further supported by grants from the German Research Foundation (DFG-TS226/1-1, DFG-TS226/3-1, SFB 1123, SFB 1321/1, and SFB TRR 152), the Nutripathos Project (ANR-15-CE14-0030), the European Research Council (ERC AdG HypoFlam 695054), the Helmholtz-Israel Cooperation in Personalized Medicine, the Marie Skłodowska Curie training network “ChroMe” (grant H2020-MSCA-ITN-2015-675610), and the German Center for Diabetes Research (DZD e.V.).

Address correspondence to: Kerstin Stemmer, Institute for Diabetes and Obesity, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany. Phone: 49.89.3187.2109; Email: kerstin.stemmer@helmholtz-muenchen.de.

Conflict of interest: RDD is currently an employee of Novo Nordisk. RDD is a cofounder of Marcadia, a company that pioneered the discovery of glucagon mixed agonists. It was acquired by Roche and later Novo Nordisk. He is a coinventor on multiple patents owned by Indiana University. MHT is a scientific advisor for Erx Biotech.

Copyright: © 2019, American Society for Clinical Investigation.

Reference information: J Clin Invest. 2019;129(10):4058–4071.https://doi.org/10.1172/JCI129195.

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