Obesity Treatments: Current and Future

In recent years, obesity has become major health problem in the United States, with 35.7% of American adults considered obese. The Centers for Disease Control and Prevention (CDC) has declared obesity a national epidemic as it is no longer considered ‘just a weight problem’ but can have grave impacts on a person’s physical, metabolic, mental health and can cause a reduced quality of life. Obesity has been associated with various life-threatening diseases including Type2 diabetes, heart disease, stroke, and various types of cancer.

The impact of obesity is not limited to serious health consequences but adds to the economic burden affecting the national healthcare system. In 2012, it was estimated that the sum of direct and indirect annual healthcare costs of obesity and obesity related illnesses totals ~$190.2 billion, which is nearly about 21% of annual medical expenditures in US. This medical expenditure is estimated to increase to $549.5 billion over the next 20 years!

Causes of Obesity:

A combination of causes and individual factors including genetics, environment, socioeconomic status and behavior are driving factors that lead to obesity. Individual behaviors, such as lack of physical activity, poor diet, medications and environmental exposures play a major role. Obesity is clinically diagnosed when an individual’s body mass index (BMI) is >30.

Current treatments for Obesity: 

1. Bariatric surgeries: These include gastric bypass surgeries alter the digestive system, limiting calorie intake and reducing body’s ability to absorb nutrients. 
   

2. Prescription drugs: In United States, currently there are four prescription weight-loss drugs approved for long term use by the U.S. Food and Drug Administration (FDA):

• Bupropion-naltrexone (Contrave): oral drug that reduces appetite
• Lraglutide (Saxenda): intravenous drug regulating appetite and caloric intake.
• Phentermine-topiramate (Qsymia): reduces appetite
• Orlistat (Xenica): interferes with fat absorption
  

3. Vagus Nerve Blocking Therapy device: An implantable device that delivers electrical stimulation to branches of the vagus nerve on theanterior abdominal wall, causing disrupted hunger sensation and induction of satiety

Future of obesity treatments using immune cells:

What new treatments are in the pipeline? Currently there are several extensive studies being conducted to test whether obesity in humans can be treated with the help of immune cells or by targeting novel biological pathways.

1. Reducing adipocytes by targeting ROR1 with CAR-T cells:

Dr. Stanley Riddell and his colleagues at NIH have been working to treat obesity by targeting and eliminating adipocytes (fat cells) using anti-ROR1 CAR-T cells.  Anti-ROR1 CAR-T is able to specifically recognize mature adipocytes and exert cytolytic activity. According to Fred Hutch, a US biomedical research center, "The only normal tissue that expresses the ROR1 protein on the surface of the cell is preadipocytes, progenitor fat cells, making them an ideal therapeutic target for immunotherapy. Experiments in nonhuman primates has demonstrated the favorable safety profile of administering anti-ROR1 CAR-T cells in vivo".

2. Sympathetic neuron-associated macrophages (SAMs):  

‍Dr. Ana Domingos and her team have shown that SAMs interact with, and influence the triggering of the neurons that release the norepinephrine, which triggers fat breakdown. SAMs can reduce norepinephrine (a fat burning hormone) in fat tissue, which blocks fat breakdown. Blocking the activity of SAMs led to increased fat breakdown, energy use and weight loss in mice. In coming years, it will be interesting to see if obesity in humans can be treated by targeting SAMs.

3. KTX-0200 developed by Kintai therapeutics:

‍Further up the developmental pipeline, scientists at Kintai therapeutics have developed KTX-0200, an oral small anti-obesity drug, which under the pre-clinical trial has shown weight loss with little changes in food consumption. Although the drug’s exact mechanism of action is not being disclosed, KTX-0200 regulates carbohydrate absorption together with increasing the colonic exposure of the key microbial metabolites that acts on human cells. Currently, Kintai is moving forward with KTX-0200 by initiating IND-enabling studies.

To date, there are several extensive studies being conducted to test whether obesity in humans can be treated with the help of immune cells including shifting macrophage phenotype from M1 to M2, activating iNKT cells or targeting novel pathways including FGF-21 and DGAT-1, however, it is still too early to comment upon their potential success, failure and long term safety profiles.

In the future, targeting multiple mechanisms that control obesity and using low dosage of treatment drugs might help in developing more effective and efficient drug treatment regimens for obesity while reducing side-effects.

Written by Manpreet Semwal, M.S., Ph.D. candidate

Edited by Alex Kirkpatrick, M.S., Ph.D. candidate

Disclaimer:

This article is for information purposes only. Consult a licensed medial provider for advice and treatment specific to you.

This article was written in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Additional References:

1. Baretić, Maja. "Obesity drug therapy." Minerva endocrinologica 38.3 (2013): 245-254.
2. BlueCross BlueShield Association. Evidence Positioning System. (3:2019). Vagal nerve blocking therapy for treatment of obesity. (7.01.150). Retrieved December 4, 2019
3. Castoldi, Angela, et al. "The macrophage switch in obesity development." Frontiers in immunology 6 (2016): 637.
4. Cawley J, Meyerhoefer C. The medical care costs of obesity: an instrumental variables approach. J Health Econ. 2012; 31:219-30.
5. Centers for Disease Control and Prevention. ‘Overweight & Obesity’. Sep 2020. https://www.cdc.gov/obesity/adult/index.html
6. Gonzalez, Anthony Michael, “Obesity in America: A growing concern’ Endocrineweb . Feb 2019. https://www.endocrineweb.com/conditions/obesity/obesity-america-growing-concern.
7. Lynch, Lydia, et al. "iNKT cells induce FGF21 for thermogenesis and are required for maximal weight loss in GLP1 therapy." Cell metabolism 24.3 (2016): 510-519.
8. National Institutes of Health. "Prescription medications to treat overweight and obesity." (2016).
9.  Pirzgalska, Roksana M., et al. "Sympathetic neuron–associated macrophages contribute to obesity by importing and metabolizing norepinephrine." Nature medicine 23.11 (2017): 1309.
10. Rebello, Candida J., and Frank L. Greenway. "Obesity medications in development." Expert Opinion on Investigational Drugs 29.1 (2020): 63-71.
11. Riddell, Stanley R., Michael Hudecek, and Christoph Rader. "Method for the treatment of obesity." U.S. Patent No. 9,163,258. 20 Oct. 2015.

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