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

Figures & data

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.

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].

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