Unlocking the potential of Reg3γ: new insights into its metabolic functions and therapeutic prospects

In a recent study published in the Experimental & Molecular Medicine Journal, researchers evaluated the physiological roles of an antimicrobial peptide (AMP), regenerating family member gamma (Reg3γ), and analyzed its therapeutic prospects for metabolic diseases. 

Study: Reg3γ: current understanding and future therapeutic opportunities in metabolic disease. Image Credit: ProximaStudio/Shutterstock.comStudy: Reg3γ: current understanding and future therapeutic opportunities in metabolic disease. Image Credit: ProximaStudio/Shutterstock.com


The current therapeutic approaches for diabetes and obesity focus on leveraging the gastrointestinal (GI) tract to promote better glycemic control and sustained weight loss. Thus, the GI tract has received more scientific focus aiming to find novel treatment strategies.

By engaging in bactericidal activity, the mouse homolog of human REG3A, Reg3γ, an AMP, works as a component of the host immune system in maintaining spatial segregation between the host and the intestinal gut bacteria.

Studies indicate that the gut microbiota regulates several elements of glucose regulation and energy homeostasis, and Reg3γ is a connection between metabolic control and gut microbiota. Although Reg3γ interacts with the gut microbiota and contributes to gut physiology, its function in metabolic diseases is unknown.

About the study

In the current review article, the researchers from the University of Michigan, Ann Arbor, United States of America (USA) examined the present understanding of Reg3γ's biology, its function in different metabolic processes, and novel potential for therapeutic approaches in metabolic disorder treatments. 

The authors reviewed various studies investigating the function and expression of Reg3γ in distinct metabolic conditions triggered by genetic modification, bariatric surgery, or nutrition.

They addressed the conflicting outcomes of research comprising the effects of underexpressed or overexpressed gut Reg3γ proteins on glucose metabolism and body weight among mouse models.

Additionally, the team analyzed the possibility of Reg3γ as a biomarker for metabolic illnesses and the potential of Reg3γ-reliant therapies for metabolic diseases.

Reg3γ's antimicrobial properties

Reg3γ generated by small intestinal enterocytes and Paneth cells exhibits antibacterial effects on gram-positive bacteria and is controlled by interleukin-22 (IL-22) and bacterial colonization. The increased Reg3γ production during bacterial infections indicates the protective role of Reg3γ against infection.

Metabolic disorders like obesity and poor glucose control impact the expression of Reg3γ. Reg3γ synthesis is evoked by glucagon-like peptide-1 (GLP-1) agonists and bile acids in the pancreas and intestine, respectively.

Reg3γ's biological properties

According to studies in mice models, Reg3γ harbors beneficial impacts in different skin diseases, including colitis, pancreatitis, psoriasis, cardiac inflammation, asthma, alcoholic fatty liver, graft-versus-host rejection during bone marrow transplantation, and damaged brain neurons.

Reg3γ is essential for wound healing, keratinocyte differentiation, and proliferation, and IL-17-induced IL-33 controls Reg3's expression. Reduced IL-33 levels in diabetes conditions cause increased inflammation and delayed wound healing. 

Role of Reg3γ in gut alterations for metabolic enhancements

Bariatric surgery, such as vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass (RYGB), results in better glucose metabolism and sustained weight loss in type 2 diabetes mellitus (T2DM) and obesity patients.

Gut anatomy manipulations in bariatric surgery elevate Reg3γ levels in the intestine and circulation, which is required for VSG's beneficial impacts. Oligofructose or inulin fiber prebiotic therapy can also increase Reg3γ synthesis in the intestine and lessen the detrimental effects of a high-fat diet on metabolic and gut health. 

Reg3γ's therapeutic implications

Studies indicate that enhancing Reg3γ or Reg3γ-linked pathways might positively impact metabolic homeostasis and may be a viable T2DM treatment strategy. Reg3γ may interact with exostosin-like glycosyltransferase 3 (Extl3) in the pancreas to exert its glucoregulatory activity and may exert its beneficial impacts through circulation.

Prebiotics, probiotics, or fermentable fiber can alter the gut microbiota makeup, increasing Reg3γ activity and positively impacting gut function, glucose homeostasis, and obesity.

Additionally, prebiotics and probiotics comprising Bifidobacterium and Lactobacillus species boost Reg3γ synthesis, and their beneficial impacts are Reg3γ-dependent. Bacterially derived metabolites such as bile acids, propionate, and lactate can stimulate Reg3γ-associated signaling and could be used to treat metabolic disorders.

Reg3γ's future perspectives

Further research is required to determine whether Reg3γ or REG3A may be combined with other gut peptide-dependent therapeutics to increase Reg3γ or REG3A activity and control glucose levels via other therapeutic targets with glucose-lowering effects.

Reg3γ is a crucial immune system element, interacting with the gut microbiota, and helps combat inflammation and oxidative stress.

Reg3γ analogs may be used to manipulate the gut to treat metabolic illnesses. Further, comprehending the endogenous Reg3γ system might aid in developing dietary supplements for leveraging its beneficial properties. 


The researchers found that Reg3γ is vital for controlling metabolism and gut microbiota makeup. They discussed the therapeutic potential of Reg3γ in managing metabolic diseases such as T2DM, non-alcoholic fatty liver disease, and obesity.

In addition, the investigators noted that further research is required to completely comprehend Reg3γ's function in metabolic regulation and develop efficient Reg3γ-dependent treatments for metabolic illnesses.

The present review article gives a thorough overview of current knowledge of Reg3γ and its potential as a therapeutic intervention for metabolic disorders.

Journal reference:
Shanet Susan Alex

Written by

Shanet Susan Alex

Shanet Susan Alex, a medical writer, based in Kerala, India, is a Doctor of Pharmacy graduate from Kerala University of Health Sciences. Her academic background is in clinical pharmacy and research, and she is passionate about medical writing. Shanet has published papers in the International Journal of Medical Science and Current Research (IJMSCR), the International Journal of Pharmacy (IJP), and the International Journal of Medical Science and Applied Research (IJMSAR). Apart from work, she enjoys listening to music and watching movies.


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