From leptin to lasers: the past and present of mouse models of obesity

ABSTRACT

Introduction: Obesity is a prevalent condition that accounts for significant morbidity and mortality across the globe. Despite substantial effort, most obesity pharmacotherapies have proven unsafe or ineffective. The use of obese mouse models provides unique insight into the hormones and mechanisms that regulate appetite and metabolism. Paramount among these models are the ‘obese’ and ‘diabetic’ mice that revealed the powerful satiety hormone leptin, revolutionizing obesity research.

Areas Covered: In this article, the authors discuss work on leptin therapy, and the clinical response to leptin in humans. The authors describe the use of modern mouse genetics to study targetable mechanisms for genetic forms of human obesity. Additionally, they describe mouse models of neuromodulation and their utility in unraveling neural circuits that govern appetite and metabolism.

Expert opinion: Combining past and present models of obesity is required for the development of safe, effective, and impactful obesity therapy. Current research in obesity can benefit from repositories of genetically engineered mouse models to discover interactions between appetitive systems and circuits. Combining leptin therapy with other satiety signals comprising the gut-brain axis is a promising approach to induce significant enduring weight loss.

KEYWORDS:

• Animal models
• anti-obesity drugs
• appetite
• gut-brain axis
• leptin
• leptin resistance
• mouse models
• neuromodulation
• obesity
• syndromic obesity

Article highlights

• Obesity is a prevalent, high-risk condition that has benefitted from mice as pre-clinical models.

• Mice with mutations in leptin and the leptin receptor laid the groundwork for our current understanding of the regulation of appetite and metabolism.

• Genetic loci that are implicated in human obesity have been targeted in mouse models to provide attractive pre-clinical models for drug discovery.

• Many current mouse models of obesity focus on dissecting neurological circuits implied in appetite and the regulation of metabolism.

• Modern obesity studies in mouse models take advantage of large repositories of transgenic mice to modulate specific cell types in the brain using optogenetics, chemogenetics, and magnetogenetics.

• Combining gut hormones that signal satiety with leptin therapy reverses ‘leptin resistance’ in rodent models of obesity and could prove to be a safe and effective obesity therapy in humans.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The authors are supported by the National Institutes of Health, via grants P30 CA56036 R01 CA204881 and R01 CA206026 from the National Cancer Institute to S Waldman and from National Institute of Diabetes and Digestive and Kidney Diseases via grant 1F30DK127639 to J Barton, the Pharmaceutical Research and Manufacturers of America (PhRMA) Foundation, the Courtney Ann Diacont Memorial Foundation, the Defense Congressionally Directed Medical Research Program via grants W81XWH-17-1-0299, W81XWH-17-PRCRP-TTSA, W81XWH-19-1-0067 and W81XWH-19-1-0263 and Targeted Diagnostics and Therapeutics Inc.