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Updated: Jul 6, 2026
Modeling and Evaluation of Murine Diabetic Cardiomyopathy Model
Published on: November 29, 2024
Development of diabesity in mice with neuronal deletion of Shp2 tyrosine phosphatase
Maryla Krajewska1, Steven Banares, Eric E Zhang
1Burnham Institute for Medical Research, University of California San Diego, La Jolla, CA 92037, USA.
Abstract:
Obesity and diabetes, termed "diabesity," are serious health problems that are increasing in frequency. However, the molecular mechanisms and neuronal regulation of these metabolic disorders are not fully understood. We show here that Shp2, a widely expressed Src homology 2-containing Tyr phosphatase, plays a critical role in the adult brain to control food intake, energy balance, and metabolism. Mice with a neuron-specific, conditional Shp2 deletion were generated by crossing a pan-neuronal Cre-line (CRE3) with Shp2(flox/flox) mice. These congenic mice, CRE3/Shp2-KO, developed obesity and diabetes and the associated pathophysiological complications that resemble those encountered in humans, including hyperglycemia, hyperinsulinemia, hyperleptinemia, insulin and leptin resistance, vasculitis, diabetic nephropathy, urinary bladder infections, prostatitis, gastric paresis, and impaired spermatogenesis. This mouse model may help to elucidate the molecular mechanisms that lead to the development of diabesity in humans and provide a tool to study the in vivo complications of uncontrolled diabetes.
Insights
Shp2 phosphatase in the adult brain is crucial for controlling food intake and metabolism. Deleting it in neurons causes obesity and diabetes, creating a model for human diabesity complications.
Area of Science:
- Neuroscience
- Metabolic Disorders
- Molecular Biology
Background:
- Obesity and diabetes (diabesity) are rising global health concerns.
- The precise molecular mechanisms and neuronal regulation of diabesity remain incompletely understood.
- Shp2 (Src homology 2-containing Tyr phosphatase) is widely expressed, but its role in the adult brain's metabolic control is unclear.
Purpose of the Study:
- To investigate the critical role of Shp2 in the adult brain for regulating food intake, energy balance, and metabolism.
- To establish a mouse model for studying the neuronal mechanisms underlying diabesity and its complications.
Main Methods:
- Generation of neuron-specific, conditional Shp2 knockout (CRE3/Shp2-KO) mice by crossing CRE3 and Shp2(flox/flox) lines.
- Phenotypic analysis of CRE3/Shp2-KO mice to assess metabolic and pathophysiological changes.
Main Results:
- CRE3/Shp2-KO mice developed obesity and diabetes, mirroring human diabesity.
- Associated complications included hyperglycemia, hyperinsulinemia, insulin/leptin resistance, vasculitis, diabetic nephropathy, and impaired reproductive function.
- The model exhibited conditions like prostatitis and gastric paresis.
Conclusions:
- Neuron-specific Shp2 is essential for maintaining adult brain control over energy homeostasis and metabolism.
- The CRE3/Shp2-KO mouse is a valuable model for elucidating diabesity mechanisms and studying in vivo diabetic complications.
