Lorcaserin, A 5-HT<sub>2C</sub>Receptor Agonist, Reduces Body Weight by Decreasing Energy Intake without Influencing Energy Expenditure

The interaction between obesity and bone metabolism is complex. The effects of fat on the skeleton are mediated by both mechanical and biochemical factors. Though obesity is characterized by higher bone mineral density, studies conducted on bone microarchitecture have produced conflicting results. The majority of studies indicate that obesity has a positive effect on skeletal strength, even though most likely the effects are site-dependent and, in fact, obese individuals might be at risk of certain types of fractures. Mechanical loading and higher lean mass are associated with improved outcomes, whereas systemic inflammation, observed especially with abdominal obesity, may exert negative effects. Weight loss interventions likely lead to bone loss over time. Pharmacological treatment options seem to be safe in terms of skeletal health; however, the skeletal effects of bariatric surgery are dependent on the type of surgical procedure. Malabsorptive procedures are associated with higher short-term adverse effects on bone health. In this narrative review, we discuss the effects of obesity and weight loss interventions on skeletal health.

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“…In a double-blind, randomized, placebo-controlled trial, lorcacerin had no effects on total BMC and total BMD [95].…”

Section: Pharmacological Management Of Obesitymentioning

confidence: 92%

Obesity and bone metabolism

2018

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“…The main mechanism of actions of the considered drugs is reduced EI 31, 32. For lorcaserin, there is even direct evidence that energy expenditure (EE) is not influenced 33. Therefore, <1% drug‐induced effect of EE was assumed.…”

Section: Methodsmentioning

confidence: 99%

Translational Modeling to Guide Study Design and Dose Choice in Obesity Exemplified by AZD1979, a Melanin‐concentrating Hormone Receptor 1 Antagonist

Gennemark

Trägårdh

Lindén

et al. 2017

CPT Pharmacom & Syst Pharma

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In this study, we present the translational modeling used in the discovery of AZD1979, a melanin‐concentrating hormone receptor 1 (MCHr1) antagonist aimed for treatment of obesity. The model quantitatively connects the relevant biomarkers and thereby closes the scaling path from rodent to man, as well as from dose to effect level. The complexity of individual modeling steps depends on the quality and quantity of data as well as the prior information; from semimechanistic body‐composition models to standard linear regression. Key predictions are obtained by standard forward simulation (e.g., predicting effect from exposure), as well as non‐parametric input estimation (e.g., predicting energy intake from longitudinal body‐weight data), across species. The work illustrates how modeling integrates data from several species, fills critical gaps between biomarkers, and supports experimental design and human dose‐prediction. We believe this approach can be of general interest for translation in the obesity field, and might inspire translational reasoning more broadly.

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“…The first, lorscaserin, is a selective serotonin 2C receptor agonist that has been shown to reduce body weight in obese patients as well as in obese patients with type 2 diabetes (352,402,518,519). The other drug approved is actually a combination of phentermine, a central norepinephrine-releasing agent, with topiramate which has been used for the treatment of epilepsy and migraine (172, 183).…”

Section: Weight Loss Drugsmentioning

confidence: 99%

Pathophysiology of Human Visceral Obesity: An Update

Tchernof

Després

2013

Physiological Reviews

1,977

1,613

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LTchernof A, Després J-P. Pathophysiology of Human Visceral Obesity: An Update. Physiol Rev 93: 359 -404, 2013; doi:10.1152/physrev.00033.2011.-Excess intra-abdominal adipose tissue accumulation, often termed visceral obesity, is part of a phenotype including dysfunctional subcutaneous adipose tissue expansion and ectopic triglyceride storage closely related to clustering cardiometabolic risk factors. Hypertriglyceridemia; increased free fatty acid availability; adipose tissue release of proinflammatory cytokines; liver insulin resistance and inflammation; increased liver VLDL synthesis and secretion; reduced clearance of triglyceride-rich lipoproteins; presence of small, dense LDL particles; and reduced HDL cholesterol levels are among the many metabolic alterations closely related to this condition. Age, gender, genetics, and ethnicity are broad etiological factors contributing to variation in visceral adipose tissue accumulation. Specific mechanisms responsible for proportionally increased visceral fat storage when facing positive energy balance and weight gain may involve sex hormones, local cortisol production in abdominal adipose tissues, endocannabinoids, growth hormone, and dietary fructose. Physiological characteristics of abdominal adipose tissues such as adipocyte size and number, lipolytic responsiveness, lipid storage capacity, and inflammatory cytokine production are significant correlates and even possible determinants of the increased cardiometabolic risk associated with visceral obesity. Thiazolidinediones, estrogen replacement in postmenopausal women, and testosterone replacement in androgen-deficient men have been shown to favorably modulate body fat distribution and cardiometabolic risk to various degrees. However, some of these therapies must now be considered in the context of their serious side effects. Lifestyle interventions leading to weight loss generally induce preferential mobilization of visceral fat. In clinical practice, measuring waist circumference in addition to the body mass index could be helpful for the identification and management of a subgroup of overweight or obese patients at high cardiometabolic risk.

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Lorcaserin, A 5-HT_2CReceptor Agonist, Reduces Body Weight by Decreasing Energy Intake without Influencing Energy Expenditure

Abstract: Lorcaserin reduces body weight through reduced EI, not altered EE or RQ.

Cited by 130 publications

References 24 publications

Obesity and bone metabolism

Obesity and bone metabolism

Translational Modeling to Guide Study Design and Dose Choice in Obesity Exemplified by AZD1979, a Melanin‐concentrating Hormone Receptor 1 Antagonist

Pathophysiology of Human Visceral Obesity: An Update

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Lorcaserin, A 5-HT2CReceptor Agonist, Reduces Body Weight by Decreasing Energy Intake without Influencing Energy Expenditure

Abstract: Lorcaserin reduces body weight through reduced EI, not altered EE or RQ.

Cited by 130 publications

References 24 publications

Obesity and bone metabolism

Obesity and bone metabolism

Translational Modeling to Guide Study Design and Dose Choice in Obesity Exemplified by AZD1979, a Melanin‐concentrating Hormone Receptor 1 Antagonist

Pathophysiology of Human Visceral Obesity: An Update

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Product

Resources

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Lorcaserin, A 5-HT_2CReceptor Agonist, Reduces Body Weight by Decreasing Energy Intake without Influencing Energy Expenditure