Discover how neprilysin (NEP) deficiency leads to late-onset obesity in mice and what this means for human weight management.
What if one of the secrets to understanding our struggles with weight gain has been hiding in plain sight, within a single enzyme found throughout our bodies? This isn't the premise of a science fiction novel but the real-world story of neprilysin (NEP), an enzyme initially studied for its roles in brain function and blood pressure regulation that unexpectedly revealed a profound connection to obesity.
The discovery emerged not from a direct hunt for obesity treatments, but as an incidental observation in research labs: mice genetically engineered to lack NEP developed late-onset obesity.
The implications of this discovery are particularly relevant to human health because unlike many genetic obesity models that show early, dramatic weight gain, the NEP-deficient mice developed their weight problems later in life—around seven months, equivalent to human middle age. This pattern mirrors the typical weight gain trajectory seen in many humans and suggests NEP may play a role in the polygenic, complex obesity that affects millions worldwide1 .
To understand why this discovery matters, we first need to understand what NEP is and what it does in the body.
Neprilysin (also known as neutral endopeptidase) is a membrane-bound metallo-enzyme widely distributed throughout the body, including the brain, kidneys, lungs, blood vessels, and other tissues. Think of it as a precision molecular scissors that specializes in cutting apart specific peptide chains. Its job is to break down bioactive peptides that play messaging roles in our body, thereby regulating their activity2 .
Molecular Scissors
NEP processes a remarkably diverse array of biological messengers, including:
Neuropeptide Y (NPY), cholecystokinin (CCK), and others that influence hunger and satiety
Atrial natriuretic peptide (ANP), angiotensin, and bradykinin that affect blood pressure
Enkephalins, substance P, and even the Alzheimer's-related amyloid beta peptide
This diverse substrate profile explains why NEP influences multiple bodily systems, from cardiovascular function to brain health—and now, apparently, body weight regulation3 .
Scientists used NEP-knockout mice—genetically engineered animals that completely lack the NEP enzyme—and compared them to normal wild-type controls.
The team tracked body weights in both female and male mice over an extended period—up to one year—to identify when weight differences emerged and how they progressed.
Using non-invasive NMR technology, researchers could precisely measure fat mass, muscle mass, and body fluid in living animals at multiple time points.
Mice were fed either low-fat or high-fat diets to examine how NEP deficiency interacted with different nutritional environments.
Scientists measured food intake, blood glucose levels, lipid profiles, and energy expenditure to understand the metabolic consequences of NEP deficiency.
The results revealed a compelling story about NEP's role in weight management:
The most striking finding was that NEP-deficient mice developed significant weight gain beginning around seven months of age, with the difference persisting and increasing throughout their lives. While wild-type mice reached a weight plateau, NEP-knockout animals continued gaining weight4 .
The NMR body composition analysis revealed that the weight gain in NEP-deficient mice was specifically due to fat accumulation, not increased muscle or fluid retention. The animals developed excessive abdominal fat and even fatty tissue around organs like the heart.
The obesity phenotype came with metabolic problems mirroring those seen in humans. Older NEP-deficient mice showed elevated serum triglycerides, decreased HDL, increased VLDL, higher blood glucose levels and impaired glucose tolerance.
Understanding how scientists study NEP and obesity requires familiarity with their essential research tools:
| Tool/Reagent | Function in Research | Specific Examples |
|---|---|---|
| Knockout mice | Genetically modified animals lacking a specific gene allow researchers to study what happens when that protein is absent. | NEP-knockout mice |
| NEP inhibitors | Chemical compounds that block NEP activity, allowing researchers to test what happens when the enzyme is disabled pharmacologically rather than genetically. | Candoxatril |
| Body composition analyzers | Non-invasive instruments that measure fat, muscle, and fluid percentages in living animals. | NMR technology |
| Metabolic cages | Specialized enclosures that precisely measure food intake, energy expenditure, and locomotor activity. | Respiration chambers |
| ELISA kits | Tests that measure specific substances in blood or tissue samples, such as hormones or metabolites. | Lipid profile assays, glucose tests |
The discovery of NEP's role in obesity opens exciting avenues for understanding and treating human weight management issues. Several key implications emerge:
Most human obesity isn't caused by a single gene but represents a complex interplay of multiple genetic factors. NEP is particularly interesting because it influences multiple biological pathways simultaneously by regulating various bioactive peptides. This makes it an attractive potential target for treating the polygenic nature of common obesity5 .
The research suggests that NEP's effect on body weight operates at least partially through appetite regulation. When the enzyme isn't working properly, the balance of hunger and satiety signals shifts toward increased food intake. This highlights the importance of peripheral mechanisms in controlling appetite.
The finding that candoxatril (a NEP inhibitor that doesn't cross the blood-brain barrier) could increase body weight in wild-type mice suggests that targeting peripheral NEP activity might be sufficient to influence body weight. This is important for drug development, as medications that don't need to enter the brain often have fewer side effects6 .
Recent human studies have strengthened the connection between NEP and body weight regulation. A 2025 investigation found that changes in serum neprilysin levels were significantly associated with BMI changes in diabetic patients, suggesting the enzyme plays a similar role in humans.
The story of NEP and obesity reminds us that scientific discoveries often come from unexpected places. What began as research into cardiovascular regulation and neurodegenerative disease has revealed surprising insights into one of humanity's most persistent health challenges.
This discovery does more than just add another entry to the list of obesity-related genes and proteins—it offers a new perspective on weight management that emphasizes the complex interplay of multiple biological systems. It suggests that the balance of bioactive peptides throughout our bodies, not just in our brains, plays a crucial role in determining our weight.
As research continues, particularly with the growing interest in incretin-based medications (like GLP-1 agonists) that also work through peptide signaling pathways, understanding enzymes like NEP that regulate these peptides becomes increasingly important. The humble enzyme that once seemed to have a purely "housekeeping" function in the body may well hold keys to future approaches for managing obesity and its related metabolic disorders.
The journey from accidental observation to potential therapeutic target exemplifies how basic scientific research continues to illuminate the complex machinery of our bodies, offering hope for addressing some of our most challenging health problems.