Targeting Fat

Obesity is considered one of the most pressing public health issues of the day. According to the Center for Disease Control, 37% of adults and 17% of children in the U.S. are obese.

The latest drug interventions work by attempting to suppress food intake, which has proven beneficial for some. However, there is still a large unmet need for new therapeutics that target the underlying molecular causes of obesity — starting with adipose (fat) tissue.

In this WEEKLY, we’ll explore the emerging view that adipose tissue is a metabolic organ undergoing pathological changes during obesity progression and find out which drugs are being developed to fight this epidemic.

Term Of The Week: Obesity

Obesity is defined as a medical condition in which excess body fat has accumulated to the extent that it is likely to have a negative effect on health. Clinically, a person is usually considered obese when their body mass index — a number obtained by dividing a person’s weight by the square of their height — is over 30 kg/m2.

Obesity is typically caused by a combination of lifestyle and genetics, although there are a few forms that are driven entirely by genetics. Lifestyle interventions that alter diet and increase exercise are successful in some; however, long-term maintenance has proven to be difficult and most patients regain any lost weight within two years.

Obesity is associated with increased risk for other metabolic, cardiovascular, and inflammatory disorders such as non-alcoholic fatty liver disease, hypertension, coronary heart disease, and stroke. It is also the primary cause of type 2 diabetes.

A Vicious Cycle

Fat used to be thought of as simply a way to store energy. Excess calories get converted into fat, which can then be broken down into fatty acids, serving as an energy source when needed.  Interestingly, the total number of the cells making up adipose tissue —adipocytes — remains the same once a person reaches adulthood. When someone gains weight they don’t increase the number of adipocytes, they increase the actual size of adipocytes. Researchers have found that location of that weight gain matters: increased adipose tissue within the abdomen is linked to metabolic disease; subcutaneous — just beneath the skin — adipose accumulation is not.

A number of things happen as abdominal adipocytes get bigger. The types of “adipokines” — metabolic signaling molecules that enable communication between adipose tissue, brain, liver, immune system, and other organs — change. An increase in fat causes adipokines to move from molecules that suppress inflammation to those that promote inflammation. This, in turn, attracts macrophages to the tissue. Macrophages are a type of white blood cell that further promote inflammation, resulting in decreased insulin sensitivity throughout the body. As adipocytes grow big, they outpace the ability of the blood vessel networks to support their growth. This results in low tissue oxygen levels, which further promotes the production of inflammatory adipokines, again contributing to insulin insensitivity. Ultimately, the abdominal adipocytes become so dysfunctional that they can no longer increase their lipid deposits, so fat expansion begins to occur in the liver, skeletal muscle, and pancreas — disrupting their functions, including insulin production (pancreas) and response (liver, skeletal muscle).

This deeper understanding of adipose tissue, as a result of obesity, has led to some new drug discovery and development approaches. The therapeutic goal: to reduce some of the systemic effects such as insulin resistance and inflammation.

Aiming For Adipokines

One of the beneficial adipokines disrupted in obesity is adiponectin. Adiponectin increases insulin sensitivity and decreases inflammation. Researchers at the University of Tokyo are conducting preclinical testing of AdipoRon, a small molecule activator of the adiponectin receptor present on the surface of muscle and liver cells. Scientists have demonstrated AdipoRon’s ability to reduce insulin resistance, abnormal distribution of adipocytes, and glucose intolerance in mice that have been bred to be a model for obesity and type 2 diabetes.

The most famous adipokine is leptin, a hormone that promotes feelings of satiety. Myalept is a leptin analog that is already approved for the treatment of the rare disorder lipodystrophy, or the irregular distribution of adipose tissue within the body. Myalept is currently in Phase II clinical testing for obesity by Aegerion Pharmaceuticals (Cambridge, MA).

Mitigating Inflammation

Since inflammation appears to be a root cause of adipose tissue dysfunction, the use of anti-inflammatories is an attractive therapeutic option. A number of different companies are testing approved or newly developed anti-inflammatory therapeutics:

  • TNF inhibitors: One of the key drivers of inflammation is the signaling molecule TNF. Remicade (Janssen Biotech, Horsham, PA) and Enbrel (Pfizer, New York City, NY) both work by inhibiting TNF. Though already approved for a range of different inflammatory conditions, both are currently in Phase I clinical studies for obesity and type 2 diabetes.
  • IL-1 beta inhibitors: A second key pro-inflammatory signaling molecule is IL-1 beta. Amgen (Thousand Oaks, CA) is conducting preclinical trials for obesity and type 2 diabetes of their IL-1 beta inhibitor Anakinra, which is already approved for rheumatoid arthritis. Novartis (Basel, Switzerland) is doing the same for their drug Ilaris, which is approved for a range of different inflammatory conditions.
  • Blocking macrophage movement into adipose tissue: Macrophages move into adipose tissue in response to signaling molecules called “chemokines.” By inhibiting chemokine signaling, researchers think they may be able to block macrophages from entering adipose tissue and worsening the cycle of inflammation. Chemocentryx (Mountain View, CA), Merck (Kenilworth, NJ), and Bristol-Myers Squibb (New York City, NY) currently have drugs in Phase II clinical studies that do just that.

White Vs. Brown Adipose Tissue

White adipose tissue (the type described above) is associated with obesity and insulin resistance. Brown adipose tissue, in contrast, regulates body temperature by actually burning calories to release heat and appears to have a beneficial metabolic impact. In most adults, however, brown adipose makes up only  ~5% of total adipose tissue. Scientists are also investigating the potential for making white adipose tissue behave more like brown adipose tissue.

Taken together, these various approaches should yield more effective treatments for obesity and insulin resistance in the coming years.

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