A BIG FAT PROBLEM
Bacon-wrapped meatloaf, chicken and waffles, cronuts! Mmm…but no wonder some of us are getting a little pudgy. According to the Centers for Disease Control (Atlanta, GA), 40 percent of adults and nearly 20 percent of children and adolescents in the U.S. are obese. Fortunately, the pharmaceutical industry is working on it.
Current drug interventions attempt to limit the amount of food patients eat, which has led to good results for some. However, a large need still exists for therapeutics that target the underlying molecular causes of obesity— starting with adipose (fat) tissue.
In this, we explore the emerging view that adipose tissue is a metabolic organ that undergoes pathological changes when we become obese. We also introduce some of the new products researchers are developing to help fight fat.
The word “obese” isn’t just another way of saying somebody is fat. In fact, it’s a medical term. The public health community defines obesity as a medical condition in which a person has accumulated so much body fat that it will likely affect his or her health. Clinically, doctors consider someone obese when their body mass index (BMI) is over 30 kg/m2. (If you’re curious, you can calculate your own BMI by dividing your weight by the square of your height.)
Interesting factoid: the number of the cells that make up adipose tissue—adipocytes—remains the same once we reach adulthood. When we gain weight, we don’t gain more adipocytes. Instead, they just get bigger. This adipose-cell elasticity may partially explain why keeping those pounds off is hard. Fat cells are always there, just waiting for a refill.
Obesity is more than a case of too many cheeseburgers. It typically stems from a combination of lifestyle and genetics, although a few forms result entirely from genetics. Some people can lose and control their weight by changing their diet and increasing how much they exercise. However, maintaining a healthy size is so difficult that most people regain any lost weight within a few years.
We all know obesity is bad for us—it’s associated with a slew of health problems, including non-alcoholic fatty liver disease, hypertension, coronary heart disease, and stroke. It’s also the primary cause of type 2 diabetes.
THE FACTS OF FAT’S LIFE
Traditionally, fat was thought of as a way to store energy. The body converts extra calories into adipose tissue, aka fat. The fat can then be broken down into fatty acids, serving as fuel when needed. Now doctors, nutritionists, and others believe that adipose tissue plays a more complicated role in our bodies’ routines.
THE DREADED MUFFIN TOP GETS MORE DREADFUL
Researchers have made a critical discovery. They’ve found that where we gain weight matters, too: increased adipose tissue within our abdomen is linked to metabolic disease. Not so with the fat just beneath our skin.
So what happens as abdominal adipocytes get bigger? Short answer: fat cell communication runs amok. Whaaa?
Yes, people, our fat cells talk to our bodies. Adipose tissue has chemical messengers called adipokines. These metabolic signaling molecules allow adipose tissue to communicate with our brain, liver, immune system, and other organs.
AN INFLAMMATORY CASCADE
Getting fatter changes our adipokines. These molecules normally suppress inflammation. When we gain fat, adipokines turn on us to become molecules that promote inflammation. The inflammation then attracts macrophages, a kind of white blood cell, to the fat tissue. They promote even more inflammation, which in turn results in decreased insulin sensitivity throughout the body. Decreased insulin sensitivity means less ability to regulate blood glucose levels, a hallmark of type 2 diabetes.
When adipocytes “fatten up,” they outpace the ability of the surrounding blood vessels to feed them. This results in low oxygen levels in the fat tissue. This “asphyxiation” leads to even more inflammatory adipokines. This promotes yet more insulin insensitivity.
What does that mean for our health? Ultimately, abdominal adipocytes become so dysfunctional that they can grow no bigger. Then fat begins to accumulate where it doesn’t belong. It shows up in the liver, skeletal muscle, and pancreas and disrupts their functions. In the pancreas, it interferes with insulin production, potentially leading to diabetes. In the liver, it’s associated with non-alcoholic fatty liver disease. Finally, in skeletal muscles, misplaced fat can impede mobility.
This deeper understanding of how adipose tissue functions has led to some new pharmaceutical approaches to treating obesity. The therapeutic goal is to reduce some of the systemic effects, such as insulin resistance and inflammation.
Adiponectin is one of the adipokines which normally increases insulin sensitivity and decreases inflammation. Researchers at the Catholic University of Korea (Seoul, Korea) are conducting phase I/IIa testing of AdipoRon, a small molecule activator of the adiponectin receptor on the surface of muscle and liver cells. Scientists have demonstrated AdipoRon’s ability to decrease insulin resistance, the abnormal distribution of adipocytes, and glucose intolerance in mice that have been bred to be a model for obesity and type 2 diabetes.
Another adipokine, leptin, may sound familiar. This hormone promotes feelings of satiety. In other words, it tells the brain that you are not hungry. Myalept is a leptin analog that the FDA has approved to treat the rare disorder lipodystrophy, or the irregular distribution of adipose tissue within the body. Researchers at Novelion Therapeutics (Vancouver, Canada) are studying the effect of Myalept in obese patients with low leptin levels. Preliminary data suggests that people taking Myalept lost more weight than those taking a placebo. Previous studies have suggested that Myalept may not help treat obesity. However, this research didn’t specifically focus on people with very low natural leptin levels. These encouraging results indicate that leptin deficiency may account for at least some types of obesity.
Inflammation appears to be a root cause of adipose tissue dysfunction. Consequently, anti-inflammatory medication presents an attractive option. A number of companies are testing approved or newly developed therapeutics that take this approach:
- 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 inhibit TNF. Though already approved for other inflammatory conditions, preliminary studies suggest that both drugs may help with glycemic control and insulin resistance.
- IL-1 beta inhibitors: Another important proinflammatory signaling molecule is IL-1 beta. Anakinra is an IL-1 beta inhibitor developed by Swedish Orphan Biovitrum (Stockholm, Sweden). It’s being studied to treat obesity and type 2 diabetes. Anakinra was approved for rheumatoid arthritis in 2001 and Deficiency of IL-1 Receptor Antagonist (DIRA) in 2020. Novartis’ (Basel, Switzerland) IL-1 beta inhibitor Ilaris is also being investigated for treating insulin resistance.
- Blocking macrophages: Macrophages move into adipose tissue in response to signaling molecules called “chemokines.” Researchers think they may be able to block macrophages by inhibiting chemokines, disrupting the inflammation cycle.
CHANGING BAD FAT TO GOOD
White adipose tissue (the type described earlier) is linked to obesity and insulin resistance. Brown adipose tissue, in contrast, regulates body temperature by burning calories to release heat. Unlike white fat, brown appears to benefit us. However, brown adipose makes up only about five percent of total body fat in most adults.
Scientists at the University of Pennsylvania (Philadelphia, PA) have identified molecular signaling pathways in white adipose tissue that convert them to energy-burning brown fat. Learning to activate that pathway pharmaceutically may eventually yield another obesity-fighting drug.
A team at Columbia University (New York City, NY)) has taken a more surgical approach to the problem. They’ve removed white adipose tissue from mice, treated it in the lab to stimulate its conversion to brown fat, and then grafted it back onto the mice. Amazingly, the “rehabilitated” tissue survived and functioned as brown fat for the two-month duration of the experiment.
And the Columbia research success goes beyond rodent fat. They’ve also figured out how to convert human white fat into brown fat in the lab. However, they have not yet carried out any grafting experiments in humans.
Taken together, these various approaches should yield more effective treatments for obesity and insulin resistance in the coming years.
Obesity, once deemed a mere consequence of caloric excess, is increasingly recognized as a multifaceted disorder rooted in genetics, lifestyle, and intricate molecular mechanisms. The interplay of adipose tissue functions and dysfunctions offers a complex portrait of this condition. As scientific investigations continue, promising therapeutic strategies are emerging, ranging from the modulation of adipokine levels to inflammatory reduction and even innovative transformations of white fat to brown fat. Collectively, these scientific endeavors illuminate a path forward, suggesting a more refined and effective therapeutic landscape for obesity and its associated conditions in the near future.
FREQUENTLY ASKED QUESTIONS
1. WHAT DEFINES OBESITY IN MEDICAL TERMS?
The public health community defines obesity as a condition where a person accumulates excessive body fat likely to affect their health. Clinically, someone is considered obese when their BMI exceeds 30 kg/m2.
2. HOW DO ADIPOCYTES, OR FAT CELLS, BEHAVE AS WE GAIN WEIGHT?
The number of adipocytes remains stable in adulthood. When we gain weight, these cells don’t increase in number but expand in size.
3. WHY IS ABDOMINAL FAT MORE CONCERNING THAN FAT BENEATH OUR SKIN?
Increased abdominal adipose tissue is linked to metabolic diseases. As these adipocytes enlarge, they disrupt the normal communication within our body, leading to inflammation and other complications.
4. WHAT ARE SOME PHARMACEUTICAL APPROACHES UNDER RESEARCH TO COMBAT OBESITY?
Researchers are exploring activators for adipokine receptors like AdipoRon, leptin analogs like Myalept, anti-inflammatory medications targeting TNF and IL-1 beta, and strategies to convert white adipose tissue to brown adipose tissue.
5. HOW DOES BROWN ADIPOSE TISSUE DIFFER FROM WHITE ADIPOSE TISSUE?
Brown adipose tissue regulates body temperature by burning calories to produce heat, making it beneficial to us. In contrast, white adipose tissue, linked with obesity, primarily serves as a storage form of energy.