#33 – Rudy Leibel, M.D.: Finding the obesity gene and discovering leptin

A pivotal experience occurred in the mid-70s when a mother, frustrated by Dr. Leibel's inability to explain her son Randall's severe obesity beyond caloric restriction, told him he 'didn't know sh*t.' This encounter spurred Dr. Leibel to retrain himself for fundamental research in understanding the disease.

In the late 1970s, adipose tissue was primarily viewed as an inert storage depot for fat. However, researchers like Jules Hirsch were beginning to consider its role as a signaling device or an endocrine organ, especially as increasing fat mass correlated with rising insulin levels.

Douglas Coleman's parabiotic experiments in the late 1970s demonstrated that OB mice were missing a humoral factor (ligand) that regulated body weight, while DB mice were missing the ability to respond to that factor (receptor). This suggested a single gene mutation in each, paving the way for leptin's discovery.

The Zucker rat is a genetic model that, similar to OB/DB mice, exhibits hyperphagia and severe obesity due to a single mutant gene. Early research on the Zucker rat challenged the lipoprotein lipase hypothesis, showing its obesity gene was in a completely different genomic location than the LPL gene.

The OB gene was cloned through meticulous genetic mapping, starting with broad chromosomal regions, and then dissecting chromosome fragments under a microscope to create finer maps. Ultimately, the breakthrough came from observing distinct leptin transcript expression patterns in OB-1J and OB-2J mice using northern blotting.

Rudy Leibel and his colleagues hypothesize that leptin's primary role is to signal to the brain when there isn't enough fat or energy to survive or reproduce. Low leptin levels act as a 'kick in the pants' to stimulate eating, rather than high levels primarily suppressing appetite.

Yes, there are rare human cases with mutations in the OB gene (leptin deficiency), which are 'curable' by leptin administration. There are also individuals with leptin receptor mutations (like DB mice), for whom there is currently no proven effective intervention.

When a human's body weight is reduced by 10-20%, there's a disproportionate reduction in energy expenditure beyond what's expected for the smaller body size. Administering low doses of leptin to these weight-reduced individuals can restore their energy expenditure back to pre-weight-loss levels, primarily via skeletal muscle.

The previous decades' intense focus on the hypothalamus as the sole integrating center for appetite has expanded. It's now understood that the central nervous system, including the brainstem, amygdala, and frontal cortex, interacts with peripheral signals (hormones, metabolites from fat and gut) to influence both conscious behaviors and unconscious physiological responses in body weight regulation.

There is evidence, both in animal and human registry data, suggesting that critical periods of development in a child's life, if exposed to an obesogenic environment (e.g., highly refined foods, high fructose), can 'imprint' changes on the regulatory system. These changes may lead to a sustained higher body weight and are not necessarily reversible even if the environmental 'insult' is removed.

Dr. Leibel believes that the effectiveness of low carbohydrate diets is primarily due to their influence on ingested behavior, particularly the 'hedonic aspects' that affect an individual's desire to eat. He suggests these diets may be more satiating, leading individuals to consume fewer calories in a way that is tolerable over the long term, unlike Ancel Keys' starvation patients.

Dr. Leibel's dream experiment involves studying the FTO gene, which carries the strongest genetic signal for common obesity through non-coding variants. He wants to understand how these variants impact the structural development and functional activity of central nervous system circuits, making individuals more susceptible to environmental triggers like high-fat diets. He believes CRISPR technology at very early stages could confirm the impact on phenotype.

Insulin resistance is complex and can manifest differentially across tissues. A person can be insulin resistant in muscle (meaning less glucose uptake by muscle), and in the liver (impaired suppression of gluconeogenesis), while still maintaining insulin sensitivity in adipose tissue. This allows fat cells to continue taking up free fatty acids and storing triglycerides, leading to fat accumulation despite overall insulin resistance.