CNS-targeting pharmacological interventions for the metabolic syndrome

Abstract

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.

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.

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.

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.