Why Target the Fat Cell?

Obesity is too much fat. Excessive fat is the result of both fat cell enlargement due to increased stores of fat (triglyceride) in each cell and an increase in fat cell number. Fat cell enlargement results from excess caloric intake being stored as triglycerides in the fat cell. Increase in fat cell number depends on the conversion, or differentiation, of "pre-fat cells" (preadipocytes) into mature fat cells (adipocytes) with the ability to store triglycerides. Controlling either increase in fat cell size or number should produce substantial therapeutic benefit.

  1. Fat cells are the main site of energy storage and release: Energy is stored as fat, and burning energy reduces fat. Our discovery technology identifies cellular-active small molecule compounds that alter the balance toward release and burning of fat versus storage, which is expected to promote effective, sustainable weight loss.
  2. Adipose tissue is an important regulatory organ, not just a storage depot: Fat cells secrete factors that regulate energy balance, i.e., storage vs burning of ingested calories, in other tissues, e.g., liver and muscle, including signaling to the brain (CNS) to control feeding behavior. Factors secreted from fat cells have been directly associated with obesity and type 2 diabetes including:
    • Leptin signals starvation vs. satiety to the brain to control feeding,
    • Adiponectin regulates insulin sensitivity in muscle and liver to regulate glucose and lipid metabolism, and
    • TNF and Resistin, which also effect tissue insulin sensitivity and energy intake and storage.
    Accordingly, pharmacologically targeting the fat cell in animal models has resulted in a broad spectrum of benefits including improved glucose homeostasis, heightened insulin sensitivity, beneficial lipid profiles and improved cardiovascular function.
  3. Targeting fat has been shown to have important effects: The thiazolidinediones (TZDs) are a class of drugs currently used to treat insulin resistance. They are agonists (activators) of the nuclear hormone receptor PPARγ in fat cells. A side effect of these drugs is weight gain. Conversely, PPARγ antagonists are a potential class of new anti-obesity drugs. In rodents, PPARγ antagonists have been shown to potentiate the effect of leptin and to stimulate adiponectin levels, resulting in increased fatty acid combustion and energy dissipation, and to render the animals resistant to diet induced obesity and insulin resistance.
  4. Adipose tissue is localized into distinct depots with varying pathogenic potentials: The accumulation of visceral (internal abdominal) fat carries a greater risk of the development of cardiovascular disease and diabetes and of consequent morbidity and mortality than peripherally distributed fat. Therefore, drugs that specifically target visceral fat are of particularly great interest. Evidence exists that fat cells residing in the visceral fat depots are regulated differently than fat cells in peripheral depots, indicating the possibility for therapeutic intervention specifically in this pathogenic fat region.


 

Fact: Death