FibroGen is actively exploring ways of using its HIF Stabilization technology to regulate general metabolism, including control over fat levels in obese patients. FibroGen's research demonstrates that many of the beneficial effects induced by exposure to moderate altitude and physical exercise can be reproduced by pharmacological HIF stabilization.

Obesity epidemic
The industrialized countries, especially the U.S., presently experience an epidemic of obesity. The National Health and Nutrition Examination Survey documented an increase of the number of obese Americans between 1994 and 2000 from 23 to 30% of the entire population. In 1991, only 5 of the 50 states showed greater than 15% of the population with a body mass index over 30. By 2002, more than 20% of the population in 30 states had a body mass index over 30. The consequences of this epidemic, both in terms of personal health and health care cost, are enormous.

Other studies show that obesity is one of several medical conditions that comprise a "metabolic syndrome". The Centers for Disease Control and Prevention (CDC) estimate that as many as 47 million Americans may exhibit metabolic syndrome characterized by insulin resistance and the presence of obesity, abdominal fat, high blood sugar and triglycerides, high blood cholesterol, and high blood pressure.

Beneficial effects of hypoxia in obese people
There are numerous medical publications that demonstrate a beneficial effect of hypoxia (e.g., exposure to high altitude) on metabolism, in general, and obesity, in particular. A recent study set out to investigate these effects in a more stringent fashion.

Patients with mild metabolic syndrome were exposed to moderate altitude (1600 m) for three weeks and monitored for six to seven weeks after they returned to their normal altitude. It was found that there was a sustained, selective loss of adipose tissue while lean body mass increased. The study authors, who had originally attempted to establish that exposure to moderate altitude was safe for patients with metabolic syndrome, not only concluded that it was safe, but might even be beneficial due to its favorable effect on the underlying condition, i.e., obesity.

HIF-mediated effects on metabolism: lessons from Chuvash
People with Chuvash syndrome, a genetic mutation that leads to persistent HIF stabilization, show the impact of the HIF system on metabolism. The incidence of obesity and the mean body mass index in people with Chuvash syndrome is significantly lower than in their spouses, who are expected to have similar lifestyles and eating habits. Other publications suggest that people with Chuvash syndrome experience additional beneficial effects of HIF stabilization related to insulin resistance, high blood glucose, atherosclerosis, and hypertension, all conditions associated with obesity. Taken together, many of these beneficial effects closely resemble those ascribed to physical exercise. The common mechanism is mild tissue hypoxia and low-level HIF stabilization.

HIF stabilization: new approach to treating obesity
FibroGen scientists have demonstrated that many of the beneficial effects induced by exposure to moderate altitude and physical exercise can be reproduced by pharmacological HIF stabilization. Several HIF-stabilizing compounds were used in studies that showed a selective loss of adipose tissues not only in normal animals but also in models of diet-induced obesity. The weight of vital organs (liver, heart, kidney) remained unchanged. In many instances the changes in gene expression induced by high fat diet, reflecting the body's altered metabolic state were completely normalized. Additional studies showed an improvement of insulin tolerance and the induction of known anti-atherosclerotic genes.

In order to achieve these effects, continuous HIF stabilization was not necessary. The metabolic benefits were readily apparent in studies where compound was given twice a week over four weeks and persisted after the last administered dose. These observations again parallel the clinical experience with physical exercise where a twice a week training schedule is clearly effective but results in, at best, a few hours of HIF stabilization.