Obesity_3_Current Theraputics

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Metabolic Disease Therapeutics Obesity Dr Garron Dodd garron.dodd@unimelb.edu.au Department of Anatomy & Physiology Copyright Regulations 1969 WARNING This material has been provided to you pursuant to section 49 of the Copyright Act 1968 (the Act) for the purposes of research or study. The contents of the material may be subject to copyright protection under the Act. Further dealings by you with this material may be a copyright infringement. To determine whether such a communication would be an infringement, it is necessary to have regard to the criteria set out in Part 3, Division 3 of the Act.
What is Obesity? Obesity is defined as abnormal or excessive fat accumulation that presents a risk to health. A body mass index (BMI) > 25 is considered overweight, and > 30 is obese. >60% 2 >35 BMI <25 BMI Adipose Tissue (fat)
Why do we become obese? Brain Insulin & Leptin Food Intake White Fat Beige Fat Energy Expenditure 1 Hormonal Inputs 2 Reward Circuitry 3 Outputs
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Current Therapeutic's - Obesity Intensive lifestyle interventions for people with obesity are associated with significant improvements in weight, however they are no effective over the long term. Regulatory bodies (FDA) use a 5% total weight loss to determine whether a drug induces a meaningful weight loss. (5% of 200kg is 10kg!) All currently licenced therapies are associated with inadequate efficacy or complications & side effects, limiting their use.
Current Therapeutic's - Obesity The US Food and Drug Administration (FDA) has approved five drug therapies to treat obesity Orlistat, Phentermine/topiramate, Lorcaserin, Naltrexone/bupropion, Liraglutide, The European Medicines Agency (EMA) has approved only three drug therapies to treat obesity: Orlistat, Naltrexone/bupropion, Liraglutide. Should medical therapies fail to achieve adequate weight loss, bariatric surgery is the only option for “some” people Good Review: https://link.springer.com/content/p df/10.1007/s13300-020-00816-y.pdf
Orlistat Orlistat is a selective inhibitor of pancreatic lipase, which thereby moderates the intestinal digestion and absorption of fat. Orlistat is indicated for patients with a BMI C 30 kg/m2 in association with other risk factors (e.g., hypertension, diabetes, hyperlipidaemia). Whilst people with obesity using orlistat lose an extra 2.9–3.4 kg weight over 12 months, gastrointestinal side effects, reduced absorption of fat-soluble vitamins and steatorrhea are commonplace. Indeed, a recent systematic review observed a mean weight loss of 3.1 kg associated with orlistat use. Additional metabolic benefits associated with orlistat use include reduced blood pressure and reduced circulating lipids. One study found the cost of weight loss per kilogram associated with orlistat was US$546, with a cost of US$71,000 per quality- adjusted life year.
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Phentermine/topiramate Phentermine is a sympathomimetic that stimulates norepinephrine (NE) release promoting energy expenditure, whilst topiramate is an anticonvulsant that augments the weight loss associated with phentermine use though the mechanism of appetite suppression is unclear. Studies of daily phentermine/topiramate describe a 6.6–8.6 kg weight loss over 12 months. Another study observed a mean weight loss of 9.8 kg associated with its use in randomised-controlled trials. Side effects include irregular cardiac function, insomnia, dizziness and paraesthesia (pins-and-needles). Whilst approved by the FDA in 2012, as a result of safety concerns the EMA rejected the The cost of weight loss per kilogram associated with phentermine/topiramate use was found to cost US $232/kg, with a cost of of $48,340 per quality-adjusted life year.
Lorcaserin Lorcaserin is as an appetite suppressant through activation of 5-HT2C (serotonin) receptors. This drugs effect on metabolism are through 5- HT2C receptors expressed on POMC neurons and was approved for use by the FDA in 2012. It is used in people with BMI C 30 kg/m2 with co-morbidity (e.g., hypertension, diabetes, dyslipidaemia). The use of lorcaserin is associated with an additional annual weight loss of about 3.2–3.6 kg as well as improvements in metabolic parameters including blood pressure and lipids. A systematic review of randomised-controlled trials using locaserin noted a mean weight loss of 3.1 kg associated with its use. Common side effects associated with lorcaserin use include headache, nausea and dizziness. 5-HT2C (serotonin) receptors are found throughout the brain! Studies exploring this therapy report a cost of US$545 per kilogram weight loss attained, with a cost of US$122,640 per quality-adjusted life year. POMC ARC Neuron Food Intake Energy Expenditur Other neurons in the brain α -MSH AgRP AgRP/ NPY MC4R 5-HT2C
Naltrexone/bupropion Naltrexone is an opiate antagonist, whilst bupropion is a weak dopamine and noradrenaline reuptake inhibitor. It is approved for use by both the FDA and EMA in the treatment of obesity. In combination, these drugs promote satiety via regulating AgRP and POMC neuons. In particular it has been shown to promote POMC cell-mediated release of melanocyte- stimulating hormone (MSH) leading to reduced food intake and increased energy expenditure. Naltrexone/bupropion is indicated for BMI C 30 kg/m2 in association with other obesity related co-morbidities. An additional annual weight loss of 4.8% total body weight (mean 4.4 kg) has been observed, with side effects including depression, nausea, headache and dizziness. Opioid receptors are expressed throughout the brain and regulate diverse functions beyond metabolism.
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Liraglutide Liraglutide is a glucagon-like peptide-1 (GLP-1) agonist, originally marketed for the treatment of type 2 diabetes (T2D). It is given as a once daily injection at a dose of 3.0 mg daily (compared with up to 1.8 mg daily for treatment of T2D). Liraglutide improves weight loss by supressing AgRP neuronal activation and promoting POMC neuronal activation thus enhancing satiety and thereby reducing food intake. It is approved by the FDA and EMA to support weight loss in people with BMI C 30 kg/m2 and obesity-related co-morbidity. Common side effects include nausea/vomiting and pancreatitis (inflammation of the pancreas). An additional annual weight loss of 5.3–5.9 kg has been observed compared with placebo. POMC ARC Neuron Food Intake Energy Expenditure Other neurons in the brain α -MSH AgRP AgRP/ NPY MC4R GLP-1 GLP-1
New Treatments Brain Insulin & Leptin Food Intake White Fat Beige Fat Energy Expenditure 1 Hormonal Inputs 2 Reward Circuitry 3 Outputs
Food Intake White Fat Beige Fat Energy Expenditure POMC Third Ventricle ARC Neuron Neurons of PVH & LH AgRP/ NPY MC4R IR LepR LepR Blood Neurons of VMH and LH Leptin Pancreas Insulin Fat AgRP AgRP/ NPY
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Targeting Insulin and Leptin Resistance https://pubmed.ncbi.nlm.nih.gov/31509751/ There are other negative regulators on insulin and leptin signalling (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354688/): Suppressor of cytokine signalling 3 (SOCS3) https://pubmed.ncbi.nlm.nih.gov/18560028/ https://www.nature.com/articles/nm1071 Phosphatase and tensin homolog (PTEN) https://www.sciencedirect.com/science/article/pii/S1550413107003051 SH2 domain-containing protein tyrosine phosphatase-2 (SHP-2, encoded by the PTPN11 gene)
ARC IR + LepR P AKT P TCPTP Intranasal Treatment
ARC IR + LepR P AKT P TCPTP Beige Fat Intranasal Treatment
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What You Need To Know Current obesity therapeutics are limited in number and efficacy. The current licenced therapeutics are: Orlistat, Phentermine/topiramate, Lorcaserin, Naltrexone/bupropion, Liraglutide, Understand the mechanism of action of each licenced treatment and discuss its limitations. A new way to treat obesity is to target insulin and leptin/resistance within the ARC. Understand the how combing your knowledge on obesity and the mechanism underlying its development and maintenance can be used to identify novel therapeutics targets

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