Lorcaserin and adiposopathy: 5-HT2c agonism as a treatment for ‘sick fat’ and metabolic disease

Abstract

Agonists of 5-hydroxytryptamine (5-HT; serotonin) receptors promote loss of excessive body fat (adiposity) and improve metabolic parameters associated with adiposity-induced adipose tissue dysfunction (adiposopathy or ‘sick fat’). By improving adipose tissue pathogenic endocrine and immune responses in overweight patients, 5-HT receptor agonists may improve metabolic disease. Lorcaserin (APD-356) is a selective 5-HT2c receptor agonist that promotes weight loss. Probably owing to its selectivity for the 5-HT2c receptor, clinical trial evidence supports that lorcaserin does not adversely affect heart valves or pulmonary artery pressure. This review examines: the mechanisms by which serotonergic pathways improve adiposity and adiposopathy; historical data and perspective regarding the efficacy and safety of prior 5-HT agonists; speculation regarding future paradigms in treating adiposopathy; and why lorcaserin may prove to be a safe and generally well-tolerated agent that not only improves the weight of patients, but also improves the health of patients.

Keywords::

• adiposity
• adiposopathy
• diabetes mellitus
• dyslipidemia
• high blood pressure
• hypertension
• lorcaserin
• obesity
• sick fat

Figure 1. Simplified relationship between serotonin (and other selected CNS factors) on anorexigenic and orexigenic peptidergic appetitive effectors within the hypothalamus [36,112].

Increased CNS serotonin, leptin and/or insulin activity increases anorexigenic POMC (which is cleaved to form melanocortins such as MSH) and CART expression, and decreases orexigenic expression of NPY and AgRP. Alterations in these peptidergic appetitive effectors contribute to ‘second order’ signaling through arcuate nucleus neurons projection to other hypothalamic regions. The net result of increased CNS serotonergic activity is increased anorexigenic and increased catabolic effects, with decreased orexigenic and decreased anabolic effects. This figure is greatly simplified, and does not show all the interconnected signaling pathways between these CNS factors.

AgRP: Agouti-related peptide; BDNF: Brain-derived neurotrophic factor; CART: Cocaine amphetamine-regulated transcript; CB1: Cannabinoid 1 receptor; CRH: Corticotropin-releasing hormone; MC3R: Melanocortin 3 receptor; MC4R: Melanocortin 4 receptor; MCH: Melanin concentrating hormone; MSH: Melanocyte stimulating hormone; NPY: Neuropeptide Y; POMC: Pro-opiomelanocortin; TRH: Thyroid releasing hormone.

Figure 2. Speculative future algorithm for the treatment of adiposopathy.

^*‘Lorcaserin’ is listed as an illustrative example of an anti-obesity agent that alone, or possibly in combination with other anti-obesity agents, may improve adiposopathy. The intent is to improve the otherwise dysfunctional adipose tissue in overweight patient, and thus correct the pathogenic endocrine and immune derangements that lead to metabolic disease.

Agonism of the 5-HT receptor promotes weight loss, which may improve fat mass-related morbidities in overweight patients [1]. Weight loss, such as through serotinergic agents, may also improve pathogenic adipose tissue endocrine and immune responses in overweight patients, which, in turn, may also improve adiposity-related metabolic disease. Adiposopathy (‘sick fat’) is a term that describes pathogenic adipose tissue (Box 1)[2]. Anatomically, adiposopathy is manifest by adipocyte hypertrophy, adipose tissue accumulation (particularly visceral adiposity), adipose tissue growth beyond its vascular supply (potentially resulting in hypoxia), limitations of adipose tissue growth (e.g., impaired extracellular matrix dissolution and remodeling), and ‘lipotoxic’ fat (free fatty acid and triglyceride) deposition in ectopic peripheral organs such as liver, muscle and pancreas [2–8]. These adipocyte and adipose tissue anatomic derangements are promoted by positive caloric balance and sedentary lifestyle in genetically and environmentally susceptible patients [3]. Pathophysiologically, these anatomic abnormalities lead to adverse adipose tissue endocrine and immune responses that contribute to metabolic disease [9]. Adiposopathy represents a unified, pathophysiologic process that is a root cause of metabolic diseases such as Type 2 diabetes mellitus, high blood pressure and dyslipidemia [10]. However, just as an increase in bodyweight may promote pathogenic adipose tissue responses [3,11], a reduction in body fat in overweight patients with metabolic diseases can often improve pathogenic adipose tissue responses, and thus improve metabolic disease [12,13].

Clinical overview

Obesity is an epidemic. In the USA, over 30% of adults are obese, with over 65% being overweight (BMI ≥ 25 kg/m²) or obese (BMI ≥ 30 kg/m²) [201]. Globally, more than 1 billion adults are overweight, with at least 300 million being obese [202]. Given the number of lives affected, obesity may represent the greatest epidemic in human existence. An increase in bodyweight is directly associated with the most common metabolic diseases encountered in the clinical practice of medicine, and increases the risk of Type 2 diabetes mellitus, high blood pressure and dyslipidemia [11,14].

Recognizing the contribution of adiposity to metabolic disease is sometimes obscured, at least in part, due to apparent ‘obesity paradoxes’. While excessive bodyweight is generally considered unhealthy, substantial data suggest that many modestly overweight patients experiencing atherosclerotic coronary heart disease (CHD) events, or undergoing CHD procedures, have better health outcomes than those who are not overweight [15,16]. Another apparent paradox is that individuals who are modestly overweight may live longer than many of those who weigh less [17]. Yet another obesity paradox is that not all overweight patients have metabolic disease, and not all patients with metabolic disease are overweight [11,18]. These apparent ‘paradoxical’ findings may be less paradoxical upon recognizing that adiposity leading to metabolic disease may be mitigated if weight gain occurs without pathogenic endocrine or immune adipose tissue responses, or at least not beyond what can be appropriately managed (metabolically) by other body tissues [11]. Conversely, some individuals (and some genetically predisposed populations) who undergo only modest fat weight gain may have pathogenic adipose tissue responses that lead to metabolic disease [6,3]. Thus, adiposity’s contribution to metabolic disease is significantly dependent upon how the fat is gained (e.g., adipogenesis), where the fat is gained (e.g., visceral versus subcutaneous adipose tissue), the effect upon adipose tissue functionality (e.g., endocrine and immune responses, as well as net free fatty acid release), and interactions (e.g., ‘cross talk’) with other body tissues (Box 1)[3,11]. From a treatment standpoint, the effectiveness of any anti-obesity therapy must take into account the degree to which it not only reduces bodyweight, but also improves adipose tissue function and patient health.

Perhaps the most cost-effective way for the individual obese patient to lose weight is through improved nutrition and increased physical activity. However, irrespective of numerous existing public health initiatives and commercial programs, interventions to promote clinically meaningful and sustained weight loss among the general population have proven to be mostly unsuccessful [19]. The ongoing obesity epidemic continues unabated. Another treatment option includes bariatric surgery, which is becoming a more frequent and widespread intervention that not only effectively treats obesity, but also effectively (and sometimes dramatically) improves adiposopathy-associated metabolic diseases [8,20].

Surveys suggest that approximately 30% of men and 40% of women report being on dietary and/or prescription/nonprescription therapy for the purposes of losing weight; many do so for reasons other than to improve their health [21]. For those with adverse health consequences, such as adiposity-related mass disorders or adiposopathy-related metabolic disease, anti-obesity drug therapies are indicated as an adjunct to appropriate nutrition and physical activity for the purpose of weight reduction. These agents are also often effective in improving adipose tissue endocrine and immune responses [13], as well as improving metabolic disease [12,22]. Unfortunately, many of the existing anti-obesity agents have adverse tolerability or safety effects that limit their use [13]. To help address these limitations on the more widespread use of anti-obesity agents, investigational combination anti-obesity agents are in late-stage development. Examples include Contrave^®, which is a fixed-dose combination of sustained-release bupropion 360 mg (a nonselective dopamine and norepinephrine-reuptake inhibitor) and sustained-release naltrexone 16–32 mg (an opioid receptor antagonist) [13,23], and Empatic™, which is a fixed-dose combination of sustained-release zonisamide 120–360 mg and sustained-release bupropion 360 mg [24]. Qnexa™ is also an investigational anti-obesity agent that is a combination agent of phentermine 3.75–15 mg and controlled-release topiramate 23–92 mg [13,25].

It is noteworthy that of the five weight loss drugs that currently have US FDA approval for weight loss, only two are approved for long-term use (up to 1 year): orlistat and sibutramine [203]. The lack of a greater number of long-term anti-obesity drug treatment options is significantly (and in some ways, uniquely) due to a dismal history of high-profile development failures and post-marketing withdrawals as the result of safety and tolerability concerns [26–28]. Another impediment to the success of anti-obesity pharmaceutical therapy is that the weight loss achieved with these agents is often variable, and when achieved, often modest. This is problematic because of the frequent perception disconnect between the degree of weight loss meeting patient expectations, and that which might be clinically meaningful in improving patient health. Strictly from a health standpoint, even a 5% weight loss may improve the adipose tissue pathogenic responses characteristic of adiposopathy [29]. Thus, even a mild-to-modest weight loss of 5–10% in overweight patients may help prevent the onset of, or provide clinically meaningful therapeutic benefits in the treatment of, Type 2 diabetes mellitus, high blood pressure and/or dyslipidemia [30,31]. The practical implication is that the focus of any weight loss investigational agent should have the following caveat:

“The development of any effective anti-obestiy agent must not only reduce fat mass (adiposity), but must also correct fat dysfunction (adiposopathy) in order to maximize metabolic health[32].’”

Serotonin pathways

Appetite is derived from the Latin word appetitus, meaning ‘desire.’ The hypothalamus is a major hub region of the brain that significantly controls desirous behavior, such as fighting, fleeing, mating and feeding. Appetite and behaviors related to feeding are dependent upon a complex and redundant system of endocrine receptors, transporters and neurocircuits that integrate signaling from the periphery (e.g., gastrointestinal system, adipose tissue, liver, muscle and pancreas) and within the CNS [33–35]. Serotonin is a biogenic amine neurotransmitter whose decrease in CNS bioavailability promotes hyperphagia and weight gain, and whose increase in bioavailability promotes decreased food intake and weight loss. Increased CNS serotonergic activity through increased G-protein-coupled 5-HT 2c receptor agonism increases anorexigenic pro-opioidmelanocortin (POMC) production in the arcuate nucleus area in the hypothalamus. Increased CNS serotonergic activity through increased G-protein-coupled 5-HT 1b receptor agonism decreases orexigenic neuropeptide Y (NPY) production, which is also in the arcuate nucleus area in the hypothalamus [36]. The net result of increased CNS serotoninergic activity is an increase in anorexigenic and catabolic effects, a decrease in orexigenic and anabolic effects, and therefore, weight loss (Figure 1). Animal studies suggest that 5-HT2c receptor null mice have depressed resting metabolic rate, as well as hyperphagia and disrupted satiety [37]. In humans, some studies suggest that 5-HT receptor agonism may increase resting metabolic rate and thermogenesis [38,39]. Other studies do not support that 5-HT agonism increases resting metabolic rate [40–42]. Thus, while 5-HT receptor agonism might possibly potentiate energy expenditure with physical activity, or perhaps even increase the thermal effect of food [43], the greatest effect of 5-HT agonism is probably due to decreased appetite and diminished food intake [44,45].

The effects of serotonin are mediated through at least 14 subtypes of the serotonin receptor family [46–48]. Applicable to this discussion are the G-coupled 5-HT2 receptor subfamily, which contains 5-HT2c, 5-HT2a and 5-HT2b receptors. The 5-HT2c receptors are located almost exclusively in the CNS, particularly in the choroid plexus, as well as limbic system structures that help control behaviors such as the hypothalamus and thalamus [47,49]. 5-HT2c receptors are involved in the brain process involving caloric balance and are a target for anti-obesity drug therapies (Figure 1). They may also be associated with CNS processes involving mood and cognition, and 5-HT2c receptors are also potential targets for epilepsy, obsessive–compulsive disorders, Parkinson’s diseases, schizophrenia, depression, anxiety, sleep disorders and drug abuse [48]. 5-HT2a receptors are likewise located in the CNS, mainly in the cortex and hippocampus [50], and are targets for various psychiatric and sleep therapeutic agents. 5-HT2a receptors may also be located on cardiac vessels and heart valves [51,52]. 5-HT2b receptors are found on cardiac vessels [51] and heart cells, such as cardiac fibroblasts and cardiac valves. An increase in serotonin stimulation of 5-HT2b receptors, as occurs with carcinoid syndrome, may cause cardiomyopathy and endocardial fibrosis of heart valves [53]. 5-HT2b receptor antagonists are being evaluated as a treatment for heart failure [54,55].

Lorcaserin

Lorcaserin is a small-molecule, selective 5-HT2c receptor agonist that is being developed as a weight-loss drug therapy. Lorcaserin (formerly known as APD-356) is chemically described as [1R]-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine [49]. Lorcaserin is a selective 5-HT2c receptor agonist with 15- and 100-fold functional selectivity versus 5-HT_2A and 5-HT_2B receptors, respectively [48,49]. Increased CNS serotonin activity through stimulation of the 5-HT2c receptor modulates caloric balance by activating the POMC system, and thus affects downstream pathways, promoting catabolism and inhibiting anabolism (Figure 1)[56,57].

In preclinical studies involving animals (rat), locaserin underwent rapid gastrointestinal absorption with maximum blood levels in approximately 0.5 h and maximum brain exposure in approximately 1 h. The elimination half-life from both blood and brain was approximately 4–6 h. The major circulating metabolite did not appreciably bind to 5-HT2 receptors [48]. In humans, the mean first day (± standard deviation) C_max for lorcaserin for 10 and 15 mg once a day, and 10 mg twice a day was approximately 157 ± 62, 230 ± 96 and 158 ± 56 nmol/l, respectively. In Phase I studies of a lorcaserin 10-mg dose, steady state was achieved by day 4, with C_max values approximately 30% higher than on day 1 [49]. In single-dose studies of oral administration to healthy volunteers, pharmacokinetic analysis [58] of lorcaserin 10, 20 and 40 mg stopped at 40 mg per day, due to disorientation and limb unawareness in a single woman subject at the 40 mg dose. A high-fat meal resulted in a 2-h delay in T_max of lorcaserin, but otherwise, the pharmacokinetic properties were unaffected. The T_max was approximately 2 h for all doses. Radiolabeled lorcaserin was mainly metabolized to a sulfamate metabolite, among other metabolites. This sulfamate metabolite represented 38% of blood radioactivity while the parent drug (lorcaserin) was 12% of blood radioactivity. The major route of elimination of radiolabel lorcaserin and its metabolites was the urine (92%), and the major urine metabolite was the lorcaserin N-carbamoyl glucuronide. Lorcaserin’s half-life was approximately 10–11 h.

Clinical efficacy of 5-HT agonists

Historical perspective of 5-HT receptor agonist efficacy

Increasing CNS 5-HT2c activity as a mechanism to promote weight loss is neither new, nor novel. Prior to lorcaserin, various 5-HT receptor agonists validated 5-HT receptors as an effective target to treat obesity. Fenfluramine was an amphetamine derivative (without psychostimulant activities) developed in the 1960’s that nonselectively stimulated 5-HT receptors, including 5-HT2c. It was approved as an anti-obesity agent in 1973 [26,36]. One of several earlier, yet illustrative, studies of fenfluramine evaluated ‘refractory’ obese women. ‘Obesity’ was defined as at least 20% above ‘standard weight’ as determined by the USA Medico Actuarial Investigation data of 1912. The study report described participants as ‘mostly middle-aged housewives’ and with no known cardiac disease or edema [59]. Of the 60 women who began the 12-week trial, 50 completed (25 in the fenfluramine group and 25 in the ‘dummy’ control group). The fenfluramine group lost 9.3 lbs, while the control group gained 0.4 lbs. The conclusion was:

“Thus, fenfluramine, although expensive, appears to be a more effective appetite suppressant than other anorectic drugs that we have so far tested. However, a mean weight loss of only 9.3 lbs (4220 g) in 12 weeks is still not very substantial.”

A review of multiple studies over the ensuing decades found that, compared with placebo: fenfluramine reduced bodyweight in obese patients by approximately 3 kg (∼6–7 lbs); more patients in the fenfluramine-treated group dropped out of studies due to adverse drug effects (9 vs 2% for placebo); and fewer patients dropped from studies due to perceived lack of weight loss (3 vs 6% for placebo) [60]. Importantly, through trials conducted in the 1970s–1990s, fenfluramine improved glucose levels in patients with Type 2 diabetes mellitus [61], and improved blood pressure [62] and lipid levels [61,63]. This helped validate that even modest weight loss through 5-HT receptor agonism had the potential to not only improve the weight of patients, but also improve the metabolic health of patients.

As levofenfluramine was thought to have potential adverse effects while providing no additional efficacy, and because fenfluramine contained both levofenfluramine and dexfenfluramine, dexfenfluramine (the active isomer) underwent clinical evaluation. The intent was to improve upon the efficacy, safety and tolerability of this class of agents through development of the dextrostereoisomer component of fenfluramine, which would presumably represent an anti-obesity agent that was a ‘pure’ serotonin receptor agonist, devoid of additional adverse antidopaminergic or sympathomimetic effects [64]. In 1996, dexfenfluramine became the first anti-obesity drug approved in the USA for long-term clinical use (then defined as over 3 months) [47]. (Sibutramine was approved in the USA in 1997; orlistat was approved in the USA in 1999) [26].

Despite the promise of both fenfluramine and dexfenfluramine, concerns persisted regarding the modest degree of weight loss, and the maintenance of clinically meaningful weight loss beyond 3 months [65]. A lack of more robust weight loss with these agents as monotherapy prompted the increased ‘off label’ use of fenfluramine combined with phentermine (a sympathomimetic adrenergic agent with limited dependence potential). This combination became popularly known as ‘fen–phen’ or ‘phen–fen.’ Such an approach and strategy had scientific backing, largely based upon a preliminary 24-week study published in 1984 [66], and especially after a series of articles published in 1992 regarding a clinical trial of 121 overweight patients, defined as 130–180% of their ideal bodyweight (IBW) as determined by the 1983 Metropolitan Life tables. In this study, at 34 weeks, fen–phen-treated subjects lost approximately 14 kg (∼31 lbs) compared with approximately 5 kg in the placebo group (∼10 lbs). Other than dry mouth, this combination treatment was generally well tolerated. Subsequent publications focused on analyses at weeks 34–104 [67], 104–156 [68], 156–190 [69] and 190–210 [70], and supported a reasonable degree of continued efficacy of the combination of fenfluramine and phentermine in treating obesity and metabolic complications for as long as 4 years [71,72]. However, less than a third of participants completed the study, and most regained weight during its latter stages [26]. Some characterized this ‘single study’ as ‘fueling the phen–fen craze’[26]. In 1997, just a little over a year after approval of dexfenfluramine, and over two decades after approval of fenfluramine, both dexfenfluramine and fenfluramine were withdrawn from the market due to an increased risk of valvular heart disease [13] – a cardiac toxicity subsequently thought due to the nonselective stimulation of cardiac 5-HT2b receptors (see discussion on safety, later).

Given that the established efficacy of these 5-HT receptor agonists was thought to be largely due to stimulation of the 5-HT2c receptor, and given that the cardiac valvular toxicity was thought to be likely due to stimulation of the 5-HT2b receptor, efforts were then directed towards the discovery and development of anti-obesity agents that were selective for the 5-HT2c receptor [44]. An example was APD-356, which was subsequently named lorcaserin [73,48].

Lorcaserin efficacy: Phase II clinical trial data

In 2005, 8 years after withdrawal of fenfluramine and dexfluramine, recruitment began on a sentential Phase II lorcaserin clinical trial. This was a 12-week, randomized, double-blind, placebo-controlled, parallel-arm study of 469 men and women (mean: ∼13% men; ∼87% women) 18–65 years of age (mean: ∼42 years) with a BMI of 30–45 kg/m² (mean: ∼36 kg/m²). Participants did not have significant dyslipidemia or hypertension, did not have diabetes mellitus, and could remain on stable antihypertensive or lipid-altering drug therapy. Participants received instructions to maintain their ‘usual’ nutritional intake. Baseline mean waist circumference was approximately 108 cm (one out of the five diagnostic components of the metabolic syndrome is increased waist circumference, which is defined as over 102 cm [>40 inches] for men, and over 88 cm [>35 inches] for women [74]). This study had a high representation of minority populations, with approximately 52% described as white, approximately 29% described as black, and approximately 18% described as being Hispanic. Among completers, the treatment groups of placebo, lorcaserin 10 mg once per day, lorcaserin 15 mg once per day, and lorcaserin 10 mg twice a day produced weight loss of 0.3, 1.8, 2.6 and 3.6 kg (p < 0.001 vs placebo for each group). The proportions of completers achieving 5% or more of initial bodyweight were 2.3, 12.8, 19.5 and 31.2%, respectively. Lorcaserin-associated weight loss also produced significant reductions waist (and hip) circumference at the 10 mg twice a day dose.

Mean baseline systolic and diastolic blood pressure was approximately 121/78 mmHg. Lorcaserin did not produce significant changes in blood pressure. Mean baseline total cholesterol (TC) was approximately 195 mg/dl (∼5 mmol/l). Lorcaserin 10 mg twice a day lowered TC by approximately 7 mg/dl (-0.18 mmol/l; p < 0.01). Mean baseline triglyceride (TG) level was approximately 134 mg/dl (∼1.5 mmol/l). Lorcaserin 10 mg twice a day lowered TG levels approximately 18 mg/dl (-0.2 mmol/l; p = not significant [NS]); Mean baseline LDL-cholesterol level was approximately 113 mg/dl (∼2.9 mmol/l). Lorcaserin 10 mg twice a day lowered LDL-cholesterol by approximately 4 mg/dl (-0.1 mmol/l; p = NS). Mean baseline HDL-cholesterol was 59 mg/dl (∼1.5 mmol/l). Lorcaserin 10 mg twice a day lowered HDL-cholesterol by approximately 4 mg/dl (∼0.1 mmol/l; p < 0.05). This mild reduction in HDL-cholesterol was not unexpected in this short trial, and consistent with a prior meta-analysis of 70 clinical trials, which concluded that while HDL-cholesterol levels often rise after weight loss stabilization, HDL-cholesterol levels typically fall during active weight loss [75]. Baseline mean fasting glucose level was approximately 92 mg/dl (∼5.1 mmol/l). Lorcaserin 10 mg twice a day significantly lowered glucose levels approximately 4 mg/dl (-0.2 mmol/l; p < 0.05). Thus, this 12-week trial supported lorcaserin as efficacious in producing progressive, dose-dependent, significant weight loss. Lorcaserin at the 10-mg twice daily dose also improved several metabolic parameters compared with placebo, even without implementation of concomitant nutritional or physical activity interventions. In total, this Phase II trial supported lorcaserin as not only improving the weight of patients, but also improving the metabolic health of patients.

Mechanisms by which 5-HT agonists may improve adiposopathy & metabolic disease

As with other interventions, the mechanisms by which 5-HT2 agonists (such as lorcaserin) improve metabolic efficacy parameters are likely multifactorial (Tables 1 & 2); (Figure 1). The primary effects of most weight loss agents that improve metabolic disease are a reduction in body fat (through reduction in appetite), and subsequent improvement in adipose tissue anatomy accompanied by improvements in adipose tissue endocrine and immune responses. Many metabolic derangements associated with increased bodyweight can be attributable to adiposopathy, or ‘sick fat,’ which may be described as having six main components, or ‘six faces’ [12]. While many of the specific effects of lorcaserin on these components have yet to be studied or reported, the following is a brief consideration of what is known about serotoninergic effects that may affect adipose tissue’s pathogenic potential.

Adipogenesis

Adipogenesis includes the recruitment, proliferation and differentiation of new fat cells. The capacity for adipogenesis is genetically and environmentally determined, and influenced by adipocyte and nonadipocyte processes [3]. If adipocyte proliferation is impaired during positive caloric balance, then existing adipocytes may undergo excessive lipogenesis and hypertrophy. This may lead to pathogenic adipocyte and adipose tissue endocrine and immune dysfunction (adiposopathy or ‘sick fat’) that, in turn, contributes to metabolic disease. Similarly, if adipocyte differentiation is impaired during positive caloric balance, then this may also result in adipose tissue dysfunction [6].

Peripheral 5-HT2 receptors (e.g., 5-HT2a and 5-HT2b) receptors may play a direct role in adipocyte differentiation [204]. However, because 5-HT2c receptors are virtually exclusive to the CNS, then 5-HT2c receptor acting agents would not likely have direct effects upon adipogenesis. However, increased activity of 5-HT2c receptors may have indirect effects on adipogenesis and adipose tissue metabolism, as is outlined in Table 1. Despite these potential indirect effects, it is likely that the greatest effect of 5-HT2c upon adipogenesis is related to the weight loss that occurs with CNS signaling that promotes negative caloric balance. In other words, the most likely mechanism by which 5-HT2c may affect adipogenesis and adipogenic markers is through a reduction in caloric balance and reduction in adiposity.

But as with other weight loss interventions, markers for adipogenesis during active weight loss should be interpreted within the context of active weight loss or maintenance of weight loss [8]. This is important because, during positive caloric balance, reduced or impaired adipogenesis contributes to pathogenic adiposopathic endocrine and immune responses that promote metabolic disease [3,6]. By contrast, the decrease in adipogenic markers with negative caloric balance and weight loss [8] does not necessarily mean that adipocytes or adipose tissue are becoming dysfunctional or ‘sick’. Instead, it is likely that adipogenesis is not physiologically appropriate (i.e., not needed) during negative caloric balance. Nonetheless, while adipogenic markers may decrease during negative caloric balance [12], the capacity for subsequent adipogenesis may be increased. In fact, enhanced preadipocyte adipogenic and antiapoptotic protein expression, and increased adipogenic potential might help contribute to the high rate of weight regain among overweight patients who lose weight [76]. It is therefore possible that one of the more important mechanisms by which weight loss improves or prevents metabolic disease is through an enhanced adipocyte capacity for unencumbered adipogenesis during future positive caloric balance, which is made even more favorable if positive caloric balance never recurs.

Pathogenic adipose tissue location

The pathogenic potential of adipose tissue is not only based upon how the fat is stored, but also where the fat is stored. While all adipose tissue stores may have pathogenic potential [3,6], visceral adipose tissue is generally considered to be more pathogenic than abdominal subcutaneous adipose tissue, which, in turn, may be more pathogenic than peripheral subcutaneous adipose tissue [3]. Visceral and other fat depots differ in genetic predisposition regarding metabolic activity, functionality, production of bioactive molecules, activity of various adipocyte receptors, and enzymatic processes involved with fat metabolism [3]. Visceral adipose tissue also differs by its location, having circulatory drainage to the liver through the portal vessel system. Visceral adipose tissue has higher sensitivity to catecholamines, and lower sensitivity to insulin compared with subcutaneous, peripheral fat. Owing to physiologic differences such as these, visceral fat accumulation is a better predictor of metabolic disease than overall adiposity, and is likely a better treatment target to reduce metabolic disease than BMI alone [77–81]. In consideration of both how and where fat is stored [3], adipocyte hypertrophy, particularly in the visceral region, will often worsen adipocyte function resulting in increased free fatty acid release into the circulation [4], and pathogenic endocrine and immune adipose tissue responses that contribute to metabolic disease [3,5,18,82].

Most weight-loss interventions result in a decrease in total body fat, including both visceral and subcutaneous adipose tissue. While not a direct measure, waist circumference is an often used surrogate for visceral fat assessment. Through direct measures of body composition by whole-body, dual-energy, x-ray absorptiometry (DEXA), as well as indirect measures, dexfenfluramine reduces bodyweight, fat mass, fat-free mass, waist circumference and hip circumference [83]. Similarly, lorcaserin reduces total bodyweight, BMI and waist circumference [49]. While animal studies support the weight reduction with lorcaserin to be preferentially fat weight loss rather than lean weight loss [48], the effects of lorcaserin on adipocyte size, adipocyte number, and more direct specific measures on visceral adiposity (DEXA) have yet to be reported.

Free fatty acid release

A net increase in free fatty acids occurs when adipocyte lipolysis exceeds lipogenesis, and is an important adipose tissue pathogenic response to adiposity and adiposopathy [5]. Increased circulating free fatty acids are lipotoxic to other body organs such as liver, muscle and pancreas, resulting in insulin resistance, diminished pancreatic insulin secretion, dyslipidemia and increased atherosclerotic coronary heart disease risk [4,11]. During negative caloric balance, lipolysis may exceed lipogenesis. Circulating free fatty acids may therefore be increased, particularly during the initial period of active and substantial weight loss [8]. This may help explain why free fatty acids may increase with short-term dexfenfluramine use (which is also associated with increased free fatty acid turnover and oxidation) [84]. Conversely, other short-term studies suggest dexfenfluramine decreases circulating free fatty acids [85], which may be related to increased insulin sensitivity associated with weight reduction. The free fatty acid effect of long-term 5-HT agonism is not well described. While a reduction in circulating free fatty acids is a potentially important (chronic) therapeutic effect of anti-obesity interventions (Table 2), the effect of lorcaserin on free fatty acids has yet to be reported.

Pathogenic adipose tissue endocrine responses

Adipose tissue is an active endocrine organ [9,86–88]. Adiposopathy results in a number of pathogenic endocrine responses that contribute to metabolic disease [3,5,6]. Interventions that improve pathogenic adipose tissue endocrine responses improve metabolic disease [12,13]. Dexfenfluramine administration may result in favorable endocrine effects, such as a decrease in insulin levels [85]. The effect of lorcaserin on some of the more commonly recognized pathogenic adipose tissue endocrine factors has yet to be reported (Table 2).

Pathogenic adipose tissue immune responses

Adipose tissue is an active immune organ [89,90]. Adiposopathy results in a number of pathogenic immune responses that contribute to metabolic disease [3,5,6]. Interventions that also improve pathogenic adipose tissue immune responses improve metabolic disease [12,13]. Animal studies suggest that fenfluramine may decrease anti-inflammatory markers such as TNF and proinflammatory interleukins; however the mechanism as to why this might occur is unclear [91]. The effect of lorcaserin on some of the more commonly recognized pathogenic adipose tissue immune factors has yet to be reported (Table 2).

Interaction & ‘cross talk’ with other body organs

Pathogenic endocrine and immune adipose tissue responses do not act alone in causing metabolic disease. Instead, the degree to which pathogenic adipose tissue responses result in metabolic disease is highly dependent upon the interaction and ‘cross talk’ with other body organs such as the nervous system, immune system, skeletal muscle, cardiovascular system, liver, gastrointestinal system, adrenal cortex and thyroid [11]. It is likely that the main beneficial effect of lorcaserin on metabolic disease is mediated through a reduction in appetite, decrease in caloric intake, and the subsequent reduction in adiposity and adiposopathy. Lorcaserin has other theoretical second-order signaling effects that could conceivably affect other body organs (Figure 1)(Table 1). However, any contribution of lorcaserin second-order signaling in improving metabolic disease, independent of the effects upon adipose tissue, has yet to be reported.

Safety & tolerability

Historical perspective of 5-HT receptor agonist safety

As previously noted, fenfluramine underwent clinical evaluation in the 1960s, and received US approval for use as an anti-obesity agent in 1973. The dextrostereoisomer of fenfluramine, dexfenfluramine, received approval in 1996. While serotonin levels were not increased by these agents, cardiac serotonergic activity was increased through stimulation of heart and heart valve 5-HT2b receptors, especially by the norfenfluramine metabolite [92]. While both were known to be associated with rare cases of primary pulmonary hypertension, it was the unexpected finding of cardiac valvulopathy that, in 1997, resulted in the ‘voluntary withdrawal’ of both fenfluramine and dexfluramine – a withdrawal that was in response to a request made by the US FDA.

The association between nonselective 5-HT receptor agonists and heart valve abnormalities was first published in the New England Journal of Medicine in 1997, through a listing of case reports of 24 women without known history of cardiac disease who received the combination of fenfluramine and phentermine [93]. In the ‘Background’ section of the publication, the authors noted the potential scope of the safety concern:

“Although the combination has not been approved by the FDA, in 1996, the total number of prescriptions in the United States for fenfluramine and phentermine exceeded 18 million.”

The authors then acknowledged the ‘serendipitous’ nature of this finding in the ‘Methods’ section, when describing how the individual case reports were found and reported:

“All the patients were identified during the course of routine evaluation for various clinical problems. No attempt was made to identify patients by reviewing databases, conducting cross-index searches of patient files, or soliciting reports of suspected cases from clinical practices. As increasing numbers of patients were identified with similar clinical features, a perceived association between these features and previous or current use of fenfluramine–phentermine evolved. The serendipitous connection between these individual cases was identified as a result of communication among several physicians beginning in May 1996.”

In other words, the data prompting the withdrawal of fenfluramine and dexfenfluramine was not derived from prospective, controlled, clinical trial data, but rather from a listing of case reports and subsequent retrospective reviews. Furthermore, while these authors did report that the cardiac valvular lesions were identical to egotamine-induced and carcinoid valve disease, and while fenfluramine was known to act through serotonergic pathways, the authors acceded to a lack of certainty regarding the potential mechanism in stating: “the precise process by which this might occur is not known”. Even as late as 2005, when describing fenfluramine and dexfenfluramine, one author stated [26]:

“Within a year of its approval, dexfenfluramine was being dispensed at a rate of 85,000 prescriptions per week. Within a year and a half of its approval, the drug was off the market, as was fenfluramine. Reports implicated the 2 drugs in a wave unusual cases of left-sided valvular degeneration – a risk that no one saw coming, and to this day, one that eludes a biomechanistic explanation.”

Despite the unclear mechanism as to why these nonselective 5-HT receptor agonists caused heart valve disease, subsequent retrospective analyses of patients administered fenfluramine and dexfluramine also supported serotonin-associated valvulopathy [94–97], which was characterized by thickening and fibrosis of heart valves. Owing to the different approaches in identifying cases, the reported prevalence of cardiac valvular regurgitation with these agents was widely variable, ranging between 6 and 33% [98]. One small, noncontrolled analysis examined patients who had previous echocardiograms performed from 1993 to 1995 while participating in a weight-loss program, and who received treatment with fenfluramine or dexfenfluramine in combination with mazindol or phentermine. Once fenfluramine and dexfluramine were withdrawn in 1997, these weight-loss program participants were invited to return for a follow-up echocardiogram. This study found that, among those who agreed to return, and who had no valvular regurgitation on previous echocardiograms, 16% (13 out of 79) had ‘new’ valvular regurgitation upon obtaining the follow-up echocardiogram. The valvulopathy appeared to be dependent upon duration, with no new cases of valvular regurgitation in patients exposed to fenfluramine or dexfenfluramine for less than 8 months [99].

Irrespective of the implications from these retrospective and uncontrolled studies, definitive conclusions were difficult to reach without the availability of hard data derived from large, prospective, blinded, randomized, controlled, confirmatory clinical trials. Nonetheless, evidence at the time suggested that the most specific heart valve abnormality associated with nonselective 5-HT receptor agonists was mild-to-more severe aortic regurgitation. The prevalence of aortic regurgitation of dexfenfluramine monotherapy, or fenfluramine in combination with phentermine appeared to be approximately 0–4%, respectively, when administered for 3 months or less, 8–13% when administered for 3 months or longer, and 14–16% when administered for over 1 year [100,13].

The accuracy of such figures derived from nonprospective data was made even more difficult because aortic regurgitation can be found in obese patients, even without use of anti-obesity drugs [101]. It was, therefore, thought reasonable to be diligent in the meticulous evaluation of cardiac valvular abnormalities in the development of any new 5-HT receptor agonist, given that:

• • Cardiac valvular abnormalities were associated with both fenfluramine and dexfenfluramine [100];

• • Cardiac valvular abnormalities were not associated with phentermine monotherapy (which was approved in 1959 [26], and is the most widely prescribed anti-obesity agent);

• • Cardiac valvular abnormalities associated with nonselective serotonin (5-HT) receptor agonists were identical to those found with carcinoid syndrome (defined as a collection of symptoms due to increased serotonin levels produced by gastrointestinal and lung tumors);

• • Similar cardiac valvular abnormalities were known to be induced by other pharmaceuticals whose mechanisms include serotoninergic pathways [102].

Paradoxically, the revelation of previously unknown, unsuspected, yet critical safety findings may have presented strategic advantages in the development of novel 5-HT receptor agonists. Investigators now knew where to focus regarding safety surveillance. Fenfluramine was in widespread clinical use in the 1960s through to the 1990s. Dexfenfluramine was highly prescribed in 1996. Their withdrawal was not due to a lack of efficacy or lack of tolerability. Instead, they were withdrawn due to rare, specific, yet critical safety findings that could reasonably be assessed in future, prospective, clinical trials of related investigational agents.

Lorcaserin safety & tolerability: Phase II clinical trial data

In the 12-week lorcaserin clinical trial described previously, lorcaserin was generally well tolerated with the most frequent adverse experiences (AEs) being transient headache, nausea and ‘dizziness’. Among the more unique aspects of this Phase II study was the degree of focus upon heart valve and pulmonary artery pressure (PAP) safety evaluations [49]. In addition to cardiovascular history, physical exam and electrocardiogram assessments performed at study visits, this clinical trial also included echocardiograms performed at screening and at the end of the study (day 85), or study exit. A pool of three qualified cardiologists at a central echocardiography core laboratory read the echocardiograms, and all were blinded to study subject identifiers. Each sonographer was given a detailed protocol, and required to interpret all images according to standard criteria. The same cardiologists, who were blinded to the treatment groups, read all echocardiograms for a given subject and included side-by-side evaluation of initial and end-of-study echocardiograms. Intravenous agitated saline was infused to optimize the evaluation of systolic PAP. Through the interpretation of almost 800 echocardiograms conducted within the framework of a protocol specifically designed to minimize reader bias, the conclusion was that lorcaserin showed no demonstrable evidence of drug-related effects on heart valves or PAP. These safety findings were consistent with the theory that the underlying cause of cardiac valvulopathy by fenfluramine and dexfenfluramine was the nonselective stimulation of the cardiac and heart valve 5-HT2b receptor [92,103–106]. It was also consistent with lorcaserin being a highly selective 5-HT2c receptor agonist with 100-fold functional selectivity versus 5-HT_2B receptors [49,48].

Lorcaserin efficacy: Phase III clinical trial data

In 2006, a much larger and more extensive Phase III lorcaserin development program began. The three sentinel Phase III trials included: Behavioral Modification and Lorcaserin for Overweight and Obesity Management Trial (BLOOM); Behavioral Modification and Lorcaserin Second Study for Obesity Management (BLOSSOM); and Behavioral Modification and Lorcaserin for Overweight and Obesity Management in Diabetes Mellitus (BLOOM-DM). Through more thorough assessments of glucose metabolism, blood pressure, lipids and other parameters associated with metabolic disease, these trials will help better define the degree to which lorcaserin not only improves the weight of patients, but also improves the metabolic health of patients. Collectively, these trials will involve thousands of patients undergoing clinical cardiovascular assessments, supported by tens of thousands of echocardiograms. As such, these clinical trials will provide much longer term clinical trial data regarding lorcaserin’s tolerability and safety.

Conclusion

Lorcaserin 10 mg twice a day promotes significant weight loss in obese patients. Lorcaserin also improves adiposopathy-related metabolic parameters such as glucose metabolism, blood pressure and lipid levels. Thus far, lorcaserin clinical trials have demonstrated no objective evidence of cardiac valvulopathy. Lorcaserin, therefore, represents an anti-obesity agent that not only improves adiposity, but also likely improves adiposopathy with potential improvements in the metabolic health of patients.

Expert commentary & five-year view

The following is a speculation as to how lorcaserin, as a representative of a safe and effective anti-obesity agent, might best fit into a future adiposity and adiposopathy treatment paradigm.

Firstly, it is possible that the term ‘obesity’ will soon become obsolete, except to the extent that it might describe excessive fat-mass-related morbidities. The degree of adiposity that contributes to the onset and/or worsening of metabolic disease varies substantially among individuals and patient populations [3,11]. A substantial range of weight reduction is required to improve metabolic disease in the individual overweight patient. This suggests that far better diagnostic criteria are needed to determine the relationship between adiposity and adiposopathy than simply height and weight (BMI) [81]. But before diagnostic criteria for the pathogenic potential of adipose tissue (adiposopathy) can be established, clinical researchers, ‘opinion leaders’ and scientific organizations must better accept that adipose tissue has pathogenic potential, at least to the extent that is known by basic scientists, clinicians and especially by patients.

Basic science data derived from countless preclinical animal and human studies support the pathogenic effects of adipose tissue, and its contribution to metabolic disease [3,5,9]. In the day-to-day practice of medicine, clinicians well-know that increases in bodyweight increases the risk of metabolic disease in their patients. This clinical experience is supported by objective data [11], and is the impetus as to why many clinicians often encourage overweight patients with metabolic disease to lose weight. In fact, the official regulatory indication for most metabolic drug therapies is as an ‘adjunct’ to appropriate nutritional therapy and increased physical activity. Similarly, many patients are cognizant that weight gain is unhealthy. Many also understand that if they are overweight and have metabolic disease, they will likely become healthier if they lose weight. Unfortunately, many challenges to the pathogenic potential of adipose tissue exist [6], and no scientific organization has yet established diagnostic criteria as to when adiposity might reasonably account for adiposopathy.

This is unsustainable, given the epidemic nature of both adiposity and associated metabolic disease. To illustrate this point, it is acknowledged that a Type 2 diabetes mellitus patient who weighs 300 lbs (with an ideal bodyweight of 150 lbs) may develop diabetes mellitus eye disease, such as disease of the retina (a thin layer of cells lining much of the orbit). The adipose tissue in this patient likely weighs over 150 lbs, and represents this patient’s largest organ by weight. It seems unreasonable to readily accept the pathogenic potential of a tissue measured in microns (retinopathy), yet deny the pathogenic potential of an organ that can be measured in hundreds of pounds, and that may constitute over half of the patient’s bodyweight. Clinicians would therefore benefit from well-founded diagnostic criteria [2] that better allow them to determine when an increase in bodyweight most increases the risk of glucose, blood pressure and lipid abnormalities, and when a reduction in bodyweight might reasonably be expected to improve them. Once such diagnostic criteria are established, then therapeutic interventions used to treat excessive body fat might better be characterized by their ability to improve the (metabolic) health of patients, rather than the degree to which they reduce the weight of patients. Furthermore, once adiposopathy diagnostic criteria are established, then treatment indications might then be established that would better allow greater access to therapies that improve metabolic disease, even if the patient is only modestly overweight. Finally, establishing diagnostic criteria and treatment indications for adiposopathy will likely prompt greater investigation, development, and subsequent regulatory approval of agents that not only reduce adiposity, but also improve multiple metabolic parameters in dysmetabolic overweight patients, even if the improvements in individual metabolic parameters with the agent would not otherwise be sufficient to currently obtain an approvable treatment indication [107].

Another example of ‘recognizing the obvious’ [10] as an approach towards improving the health of overweight patients is to acknowledge that public health and ‘diet’ initiatives, however well-intentioned and however effective in an individual patient, have failed to reverse the ‘obesity epidemic’ [202]. Furthermore, given all the redundant and recalcitrant body systems that prioritize avoidance of starvation, it is unlikely that a single pill or even a combination of pills will cause the 300-lb patient previously described to achieve an ideal bodyweight. In the not too distant future, bariatric surgery may become recognized as the treatment of choice for significantly overweight patients, which is an approach that some might argue is already most consistent with an objective assessment of current clinical trial data [8]. If advancement in science continues to support these concepts, if these concepts become accepted, and if lorcaserin is approved, then the following may be better supported:

• • Adipose tissue has no less pathogenic potential than the ‘opathies’ of other body organs [13];

• • Adiposopathy is a better treatment target to improve metabolic disease in overweight patients than adiposity alone [81];

• • Just as with the ‘opathies’ of numerous other body organs, diagnostic criteria for adiposopathy need to be established [2];

• • Just as with the ‘opathies’ of numerous other body organs, treatment indications for adiposopathy need to be established [107];

• • Bariatric surgery not only improves the weight of patients, but also improves the metabolic health of patients, with effectiveness in patients with a BMI greater than 30 kg/m²[8];

• • Bariatric surgery techniques will continue to improve with regard to safety, such that undergoing bariatric surgery will become viewed as being no more unusual (and performed no less frequently) than other common surgeries, such as gall bladder or hernia surgery [8,108];

• • Improved surgical techniques, improved surgical efficacy, improved surgical safety, and continued data regarding reduction in overall mortality will make bariatric surgery increasingly more cost effective [8];

• • Adiposity and adiposopathy drug therapy, such as lorcaserin, will best be indicated for markedly overweight patient with metabolic disease who are not surgical candidates, or for modestly overweight patients with adiposopathy wherein a reduction in 5–10% of bodyweight would be expected to improve metabolic parameters associated with metabolic disease. This may prove to include patients with metabolic disease who have BMI as low as 25–30 kg/m².

Given these ‘speculations,’ Figure 2 describes a conceivable future algorithm for the treatment of adiposopathy.

Table 1. Adipogenic and adipose tissue metabolic effects of illustrative CNS factors promoted by 5-HT2c agonism.

CNS factors	Adipogenic and adipose tissue effects	Ref.
POMC	Lorcaserin increases POMC release. POMC deficiency results in a clinical syndrome of early-onset obesity (due to deficiency in second-order downstream signaling that otherwise promotes catabolism and suppresses anabolism), adrenal insufficiency (due to deficiency of ACTH), and red hair (due to deficiency of melanocortin receptor stimulation). The net effect of POMC on adipocyte proliferation and differentiation is not well described	[109]
TRH	Increased CNS POMC release increases TRH release. TRH stimulates thyroid hormone release from the thyroid, and increases catabolism. Thyroid hormone helps regulate adipogenesis, and may promote adipocyte proliferation. Thyroid hormone also increases metabolic rate, which may result in negative caloric balance, increased lipolysis and reduced adipocyte size	[110,111]
CRH	Increased POMC release increases CRH release. CRH stimulates cortisol release from the adrenal gland. The effect of glucocorticoids on adipose tissue are multifactorial. Glucocorticoids decrease adipocyte proliferation and increase adipocyte differentiation, both of which promote adipocyte hypertrophy, which, if excessive, is pathogenic. Glucocorticoids are catabolic to adipose tissue (and other organs such as muscle). Therefore, excessive glucocorticoids may induce lipolysis resulting in smaller peripheral subcutaneous adipocytes. Glucocorticoids are anabolic with respect to caloric balance (and liver), and increase appetite. Due to an increase in glucocorticoid receptors in visceral adipose tissue, excess glucocorticoid levels along with glucocorticoid-induced increases in caloric balance (appetite) may disproportionately increase visceral adipose tissue accumulation (visceral adiposity), visceral adipocyte hypertrophy, resulting in pathogenic endocrine and immune responses. Furthermore, glucocorticoid-induced insulin resistance promotes hyperinsulinemia, which may overwhelm the relatively minor lipolytic effects, and thus promote increased triglyceride storage in visceral fat cells resulting in yet further adipocyte hypertrophy and further pathogenic adipose tissue responses	[3]
CB1R	Increased POMC release decreases CB1R stimulation. Decreased CB1R activity increases catabolism and decreases anabolism. Stimulation of adipocyte CB1Rs increases intracytoplasmic cAMP; CB2R activation decreases cAMP. An increase in adipocyte cAMP increases adipogenesis. Impairment of the endocannabinoid system (such as through CB1R antagonists) reduces caloric balance, mainly through CNS effects that reduce appetite. The net result of CB1R antagonists is a reduction in body fat, reduced adipocyte fat and maintenance of the existing number of functional adipocytes	[22]
MC3R/MC4R	Increased POMC release increases MC4R/MC3R activity. Increased MC4R/MC3R activity increases catabolism. Inhibition of these CNS melanocortin receptors may promote lipid uptake, triglyceride synthesis, and fat accumulation in adipocytes, independent of food intake and before changes in adiposity. Agonism of CNS melanocortin receptors reduces adipogenesis, at least in part through reducing the orexigenic and adipogenic effects of other CNS factors, such as NPY	[112–114]
BDNF	Increased POMC release increases BDNF release. BDNF increases catabolism. A decrease in CNS BDNF gene expression is thought to possibly account for the obesity found with WAGR syndrome. The effects of BDNF on adipogenesis are not well defined	[115]
MCH	Increased POMC release decreases MCH release. MCH decreases anabolism. MCH deficiency decreases body weight due to hypophagia; MCH overproduction increases body weight. While functional MCH signaling pathways may exist in adipocytes, the effects of MCH on adipogenesis are not well defined	[116]
Orexin	Increased POMC release decreases orexin. Orexin decreases anabolism. Increased CNS orexin stimulates food intake, while decreased orexin causes hypophagia. Although functional orexin receptors may exist in adipose tissue, the effects of orexin on adipogenesis are not well defined	[117]

Lorcaserin increases POMC release, which has second-order signaling resulting in mixed effects upon adipogenesis and adipocyte metabolism. The physiological and pathophysiological clinical implications of these effects must be interpreted within the context of active weight gain or weight loss (see text). Further investigation is needed before speculating on whether any of these effects represent independent mechanisms that improve adipose tissue function, affect other body organs, and thus independent mechanisms that improve metabolic disease. Most current evidence supports that the mechanism accounting for lorcaserin’s effects upon adipogenesis, adiposity and adiposopathy is the promotion of reduced caloric balance and weight loss, mainly achieved through reduced appetite.

5-HT2c: 5 hydroxytryptamine-2c; ACTH: Adrenocorticotropic hormone; BDNF: Brain-derived neurotrophic factor; CB1R: Cannabinoid 1 receptor; CRH: Corticotropin-releasing hormone; MC3R: Melanocortin 3 receptor; MC4R: Melanocortin 4 receptor; MCH: Melanin-concentrating hormone; NPY: Neuropeptide Y; POMC: Pro-opiomelanocortin; TRH: Thyroid-releasing hormone; WAGR: Wilms tumor, aniridia, genitourinary anomalies and mental retardation.

Table 2. Examples of treatments for adiposopathy and their effects upon illustrative and selected adipose tissue factors that may contribute to metabolic disease.

Intervention	May affect glucose metabolism, blood pressure and lipid metabolism					May affect glucose metabolism		May affect blood pressure		May affect lipid metabolism
	Visceral adipose tissue^*	Free fatty acids	Leptin	Adiponectin		TNFα		Renin–angiotensin–aldosterone enzymes		Androgens	Estrogens
Nutrition and physical activity	↓	↓	↓	↑		↓		↓		↓ (women), ↑ (men)	↓/– (men)
PPAR-γ agonists^§ (pioglitazone, rosiglitazone)	↓/–	↓	↓/–	↑		↓		–		↓	↓/– (men)
Orlistat	↓	↓	↓	↑		↓		?		↓ (women)	?
Sibutramine	↓	↓	↓	↑/–		?		?		↓ (women)	?
Cannabinoid receptor antagonists	↓	↓	↓	↑		↓		?		?	?
LAGB^‡	↓	?	↓	↑		↓		?		?	?
Gastric bypass	↓	↓^‡	↓	↑		↓		↓		↑ (men)	↓ (men)
Lorcaserin	↓ [49]	?	?	?		?		?		?	?

↑: increased; ↓: decreased; ?: unreported; -: neutral effect.

^*Visceral adiposity may be approximated by measurements of waist circumference

^‡Acutely, (e.g., 1 month) free fatty acids may be increased during rapid weight loss.

^§PPARγ agonists may: increase adipose tissue proliferation and differentiation; favorably alter the visceral-to-subcutaneous adipose tissue deposition ratio; reduce hepatic fat deposition, and; have improved other aspects of adipose tissue function [4,12,13]. While some of the weight gain associated with PPARγ agents is due to fluid retention, much of the weight gain observed with these agents used to treat metabolic diseases traditionally associated with fat weight gain are (paradoxically?) due to promoting increased amounts of functional adipose tissue.

PPARγ: Peroxisome proliferators-activated receptor-γ.

Data from [8,11,13].

Box 1. Adiposopathy (‘sick fat’): summary of causality, as well as examples of anatomical, pathophysiological and clinical manifestations.

Causes of adiposopathy

• • Positive caloric balance [5]

• • Sedentary lifestyle [5]

• • Genetic predisposition, such as in Asian Indians and Pima Indians [3]

• • Environmental causes, such as hypercortisolemia [3,5,12]

Anatomical manifestations of adiposopathy

• • Adipocyte hypertrophy [3]

• • Visceral adiposity [3]

• • Growth of adipose tissue beyond its vascular supply

• • Ectopic fat deposition in other body organs [4]

Pathophysiologic manifestations of adiposopathy

• • Impaired adipogenesis, such as impaired adipocyte proliferation and/or differentiation [3]

• • Increased circulating free fatty acids [4]

• • Pathogenic adipose tissue endocrine responses, for example increased leptin, increased TNFα, decreased adiponectin, and increased mineralocorticoids [3,6,8]

• • Pathogenic adipose tissue immune responses, for example a net increase in proinflammatory responses through increased TNFα and decreased adiponectin [3].

Pathogenic interactions or pathogenic ‘cross talk’ with other body organs, for example liver, muscle and CNS[11]

Clinical manifestations of adiposopathy[3,6]

• • Hyperglycemia

• • High blood pressure

• • Dyslipidemia

• • Metabolic syndrome

• • Atherosclerosis

• • Fatty liver

• • Hyperandrogenemia in women

• • Hypoandrogenemia in men

• • Cancer

Key issues

• • Lorcaserin is a selective 5-hydroxytryptamine (serotonin) 2c (5-HT2c) receptor agonist that improves adiposity by promoting weight loss.

• • Through reduction in adiposity and waist circumference, lorcaserin improves adiposopathy, and thus improves multiple metabolic parameters associated with metabolic disease.

• • Lorcaserin is generally well-tolerated, with the most common adverse experiences being transient headache, nausea and ‘dizziness’.

• • Thus far, clinical trial results support that lorcaserin has no adverse effects on heart valves or pulmonary artery pressures.

• • Through second-order signaling, lorcaserin may have theoretical benefits on adipose tissue metabolism, and thus theoretical benefits in treating metabolic disease that may be independent of weight loss. However, available evidence suggests that the main improvement in adipose tissue function is through its promotion of weight loss.

• • Lorcaserin’s effectiveness in treating patients with diabetes mellitus, hypertension and dyslipidemia (as well as epilepsy, obsessive–compulsive disorders, Parkinson’s disease, schizophrenia, depression, anxiety, sleep disorders and drug abuse) await clinical trials, or the results of clinical trials in these specific patient populations.

• • Based upon available evidence, lorcaserin appears to be a generally safe and well-tolerated agent that not only improves the weight of patients, but also improves the metabolic health of patients.

Financial & competing interests disclosure

Harold Bays has served as a consultant, and received research grants from Arena Pharmaceuticals. He has also served as an advisor for regulatory matters concerning drug development, been a primary investigator for over 400 clinical trials, and served as a consultant and speaker for multiple pharmaceutical companies. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript

Notes

Adiposity and obesity can also result in diseases related to fat mass, as well as diseases related to fat dysfunction (adiposopathy).