Targeting Autophagy for Obesity Treatment
Obesity is closely connected to autophagy, a vital cellular process impacting metabolic health. Targets which affect autophagy may therefore be a promising therapeutic approach.
Obesity is closely connected to autophagy, a vital cellular process impacting metabolic health. Targets which affect autophagy may therefore be a promising therapeutic approach. Using Causaly, DDIT4 was identified as a target which affects autophagy in obesity, shedding light on potential therapeutic interventions for obesity and its associated comorbidities.
The Link Between Autophagy and Obesity
The global obesity crisis has reached epidemic proportions, causing over 2.8 million deaths each year.¹ Those affected face increased risk of developing conditions including diabetes, hypertension and cancer, making obesity a severe threat to human health. The complexity of this disease becomes even more apparent when considering the role of metabolic health and autophagy.
In the complex landscape of metabolic health, autophagy and obesity emerge as deeply interconnected phenomena. Autophagy is responsible for maintaining cellular homeostasis and organ function by selectively removing toxic proteins, lipids and organelles from cells.² The dysregulation of this process can lead to fat accumulation, inflammation and metabolic disorders.³ Exploring targets associated with autophagy may the therefore be a promising approach for the management of obesity.
Identifying Autophagy Targets for Obesity
Over 5,000 targets for obesity were identified from the literature, using Causaly. Approximately 1,000 of these targets affect autophagy in this disease. As autophagy can downregulate obesity, targets were refined by those that induce this process, revealing approximately 450 targets. Almost 150 targets have been reported in primary data in the last 5 years, 100 of which have been studied in vivo, Figure 1. Examination of the evidence uncovered DNA damage inducible transcript 4 (DDIT4) gene as a potentially interesting autophagy-related target for this disease.
Regulating Autophagy: DDIT4
DDIT4, also known as REDD1, encodes a protein which regulates cell growth, proliferation by inhibiting mTOR1.⁴ Obesity is marked by the hyperactivation of the mTOR1 pathway in adipose tissue,⁵ therefore, regulators of this pathway, such as DDIT4, are of interest as therapeutic targets.
A recent study found that docosahexaenoic acid (DHA) supplementation prevented the decline of muscle fiber conversion and exercise capacity in mice on a high-fat diet.⁶ DHA was shown to enhance mitochondrial biogenesis and skeletal muscle fiber remodeling via DDIT4 signaling.⁶ As DDIT4 can positively regulate autophagy,⁷ it was postulated that DDIT4 may restore autophagy flux in the skeletal muscle of obese mice, thereby promoting mitochondrial biogenesis.
The role of autophagy in obesity is pivotal, serving as a nexus for metabolic imbalances, inflammation, and insulin resistance. Identifying and understanding targets like DDIT4 that influence autophagy offer a promising pathway for obesity treatment. These insights could lead to more targeted therapies, potentially alleviating obesity-related comorbidities and improving global health.
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