Obesity pharmacotherapy: current perspectives and future directions

Abstract

The rising tide of obesity and its related disorders is one of the most pressing health concerns worldwide, yet existing medicines to combat the problem are disappointingly limited in number and effectiveness. Recent advances in mechanistic insights into the neuroendocrine regulation of body weight have revealed an expanding list of molecular targets for novel, rationally designed antiobesity pharmaceutical agents. Antiobesity drugs act via any of four mechanisms: 1) decreasing energy intake, 2) increasing energy expenditure or modulating lipid metabolism, 3) modulating fat stores or adipocyte differentiation, and 4) mimicking caloric restriction. Various novel drug candidates and targets directed against obesity are currently being explored. A few of them are also in the later phases of clinical trials. This review discusses the development of novel antiobesity drugs based on current understanding of energy homeostasis.

Fig. (1)

Neuroendocrine control of energy homeostasis (details in text).

1. afferent system generates signals released from adipose tissue (leptin), pancreas (insulin) and stomach(ghrelin)

2. central processing unit present in hypothalamus having two set of neurons: orexigenic and anorexigenic neurons

3. efferent system carries out anabolic and catabolic signals by modulating feeding behavior or energy expenditure

NPY/AgRP= Neuropeptide Y/ Agouti related peptide; POMC/CART= Pro-opiomelanocortin/ Cocaine and Amphetamine Related Transcript; NPY Rec= Neuropeptide receptor; MCH= Melanin Concentrating Hormone; α MSH= α Melanocyte Stimulating Hormone; Mc4R= Melanocortin receptor; TRH= Thyrotrophin Releasing Hormone; CRH= Corticotrophic Releasing Hormone

Fig. (2).

Short and long term regulation of energy intake (details in text) NTS= Nucleus tractus solitarius ; CCK= cholecystokinin; GLP1= Glucagon like peptide1

Fig. (3).

Strategies to overcome leptin resistance (Details in text) Step 1: Modified leptin bypassing normal brain transport or use of intranasal leptin Step 2: Stimulating leptin signaling:

1. Activating STAT3, an important transcription factor recruited during leptin signaling

2. SOCS3 & PTP1B antagonists (inhibition of autoinhibitory factors involved in leptin signaling)

Step 3: Melanocortin Mc4 receptor agonist (downstream pathway of leptin signaling exerting anorectic and thermogenic effect ) Step 4: Stimulating melanocortin signaling: SIM1 stimulation (a transcription factor that acts as a mediator for the anorectic, but not thermogenic effects of melanocortins) ARC= Arcuate nucleus; PVC= paraventricular nucleus; JAK= Janus kinase; STAT3=Signal transducers and activators of transcription; SOCS3= Suppressor of cytokine signaling-3; PTP1B= Protein tyrosine Phosphatase1 B; α MSH= α Melanocyte stimulating hormone; Mc4R= Melanocortin receptor; TRH= Thyrotrophin Releasing Hormone ;CRH= Corticotrophic Releasing Hormone; SIM1= Single- minded homologue 1.

Fig. (4).

Classification of antiobesity drugs according to mechanism of action (details in text) WAT= White adipose tissue; BAT= Brown adipose tissue; PPAR= Peroxisome proliferator-activated receptors;SOCS3= Suppressor of Cytokine Signaling-3; PTP1B= Protein Tyrosine Phosphatase1B; SIM1= Single- minded homologue 1; CNTF= Ciliary neurotrophic factor; 5HT= serotonin; MCH= Melanin concentrating hormone; CCK= cholecystokinin; GLP1= Glucagon Like peptide1; PP= Pancreatic polypeptide; FAS=Fatty acid synthase; CRF= Corticotrophin releasing factor; DGAT= Diacylglycerol acyltransferase; SCD= Stearoyl CoA desaturase; ACC= Acetyl coA carboxylase; HSD= Hydroxysteroid dehydrogenase.

Fig. (5).

Mechanism of uncoupling proteins. UCP= Uncoupling protein UCP1: Unique to brown fat UCP2: Widely distributed in the body UCP3: Mainly in skeletal muscle Stimulation of UCP3 might have beneficial effects for obesity management ETS= Electron transport chain; ADP= Adenosine diphosphate; ATP= Adenosine-5'-triphosphate; NADPH= Nicotinamide adenine dinucleotide phosphate H⁺