Feature: Big questions about obesity

This feature appeared in the July/August 2009 issue of Australian Life Scientist. To subscribe to the magazine, go here.

Professor Mark Febbraio says there’s a widespread view in the community that obese and overweight people are the victims of their own weakness; if they resolved to eat less and exercised more, they’d be fine.

This is not a view to which the Baker International Diabetes Institute researcher subscribes. How likely is it, he asks, that the 54 per cent of Australians who are overweight or obese, and at risk of type 2 diabetes, simply lack willpower?

“It’s not a disease of weakness,” says Febbraio. “It’s a physiological disorder in which the signals to decrease appetite are either dysregulated where they are secreted in the periphery or where they are received in the hypothalamus.”

Where most researchers are probing the intricate neurohormonal circuitry of the hypothalamus, which regulates appetite, Febbraio and his colleagues have focused on the possibility that obesity arises from errors in neurohormonal signalling from muscle and fat back to the brain and the hypothalamus, the seat of basic drives including hunger.

They have developed an extensive mouse metabolism phenotyping collection and are focusing on pathways that upregulate energy expenditure.

“Obesity research falls into two basic categories: looking for therapeutic targets that increase energy expenditure, or decrease food intake. Most researchers focus on the brain, particularly the hypothalamus, but the hypothalalmus controls so many aspects of metabolism that there is always a high risk of off-target effects. For example, the anti-obesity drug Rimonabant is not available in Australia because it can cause depression and anxiety and it is not recommended for people with mood disorders.”

Febbraio’s preference for studying peripheral signalling pays homage to Jeffrey Friedman, whose Rockefeller University research team discovered the hormone leptin in the 1990s.

Secreted by adipocytes – the specialised cells that store fat – leptin acts upon neuropeptide Y receptors in the hypothalamus to reduce appetite when the body has stored sufficient fat reserves to survive through hard times.

Friedman discovered that a strain of laboratory mouse that develops a voracious appetite and becomes massively obese has a mutation in the gene than encodes leptin. It disrupts the signal from the adipocyte to the brain to regulate satiety.

“I think Jeff Friedman should be given a Nobel,” Febbraio says. “Leptin didn’t end up being a panacea for obesity, but he provided the first real evidence that a canonical signal from the adipocyte to the brain regulates appetite. When I think about disease susceptibility or protection, few people in the population who are susceptible to diabetes are not included in the 80 per cent of individuals who get metabolic disease if they over-eat.”

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Connections

Febbraio characterises himself as a “Johnny-come-lately” to the field of obesity and diabetes research. “My background is in exercise physiology,” he says. “In the late 1990s my lab and our collaborators in Copenhagen made the first observation that interleukin-6 (IL-6), a pleiotropic cytokine expressed in many tissues, was synthesised and secreted by contracting skeletal muscle. Until that discovery, interleukin-6 was thought to be mainly involved in immune-system function and inflammation.

“People regarded us as crazy or as heretics because, at the time, adipose tissue was the only known endocrine secretory metabolic organ. But several studies from around 1985 onwards had suggested adipocytes are more than just a storage site for fats.

“We wondered what IL-6 originating in skeletal muscle might be doing. We did a number of experiments that showed IL-6 increased fat oxidation during exercise, indicating it had a role in signalling.

“Since the 1950s, people had been looking for a mysterious ‘work factor’ secreted by muscle, that signals the liver to liberate glucose at the onset of exercise. In 2004, we identified IL-6 as the signal. It was the first time muscle had been shown to be an endocrine organ; we discovered the first ‘myokine’. Since then we’ve been working to identify others.

“It also acts as an insulin mimetic in muscle and fat cells, in that like insulin, IL-6 translocates specific glucose transporters from intracellular pools to the cell membrane where they promote cellular uptake of glucose. It’s almost as potent as insulin itself.”

Febbraio’s group went looking for other IL-6 family cytokines with possible roles in energy metabolism, and showed that Ciliary Neurotrophic Factor (CNTF) prevents obesity in mice by increasing energy expenditure. Another highly pleiotropic cytokine, Leukaemia Inhibitory Factor (LIF), also does part-time duty as a myokine – the common link is that all three molecules signal via the same receptor, glycoprotein 130 (gp130).

Brain-derived neurotropic factor (BDNF) is another myokine secreted by contracting muscle cells, which activates 5’ AMP-activated protein kinase (AMPK). AMPK is an enzyme involved in energy homeostasis. By stimulating fatty-acid oxidation in the liver, it regulates serum cholesterol, triglycerides and lipids.

---PB--- The road to the clinic

CNTF looked a promising anti-obesity candidate. New-York based biotechnology company Regeneron supplied Febbraio’s group with “copious amounts” of CNTF for experimentation and set up a clinical trial.

But CNTF circulates at low levels, has a brief half-life and has relatively few receptors in the liver; the very high concentrations required to produce a therapeutic effect caused some trial patients to develop CNTF antibodies.

Febbraio and his colleagues are attempting to create modified ligands for gp130 receptors that would be up to 10 times more potent than the native molecule, so it could be administered at concentrations low enough to remain below the immune system’s radar. They have developed one promising candidate, and are now working to increase its half-life in the body. Febbraio says it is still a long way from clinical trials.

“We published a really exciting finding last year that the 70-kilodalton heat shock protein [HSP70] prevents obesity and insulin resistance, and we already have an activator of HSP70. We had made a HSP70 transgenic mouse and reported it at conference. A small Hungarian biotech company, N-Gene, had a representative at the conference, and they got us to test a compound that prevents insulin resistance and increases fat oxidation in genetically obese mice by activating HSP70. I’m now a principal research advisor with the company.”

Interestingly, says Febbraio, HSPs also block pathways involved in inflammation; they are upregulated by anti-inflammatory salicylates like aspirin. A salicylate derivative is currently in a major multi-centre clinical trial to determine if it reduces type 2 diabetes.

Salicylates upregulate energy metabolism in two ways: by blocking serine and threonine kinases that increase insulin resistance; and by inhibiting inflammation. He and his colleagues have a strong interest in the nexus between inflammation and insulin resistance. “Type 2 diabetes is a low-grade inflammatory disorder that leads to dysregulation of glucose and fat metabolism.”

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Managing a future

Febbraio suggests he has been “incredibly lucky” in his research career, which has taken some improbable paths since he was an undergraduate at Victoria University in Footscray, where he also completed his PhD in exercise physiology. He then found a job as a lecturer in the University of Melbourne’s Department of Physiology, but realised early on that teaching was not his ideal vocation.

“I spoke to the head of department and told him I wasn’t enjoying teaching. He suggested, in a kind way, that I might have an attitude problem and suggested that I go into full-time research.

“It wasn’t something I had really thought about, but a friend who was head of physiology at RMIT University offered me a full-time research position, on the condition that I had to find my own salary after three years. I applied for a National Heath and Medical Research Council Senior Fellowship and, to my surprise, I got one. And since then, I’ve been able to progress in the NHMRC system.

“In 2006, the Baker Institute invited me to join them and I relocated my laboratory of about 20 people to become the head of basic science in obesity metabolism at the Baker.

“I heard a Nobel laureate say that, if you want to succeed as a scientists, you surround yourself with people smarter than you are. I’ve done that, and I look after them to keep them happy. Good management is an enormous part of being a successful scientist. I suppose that if I wasn’t an effective manager, and didn’t have some good ideas – along with ones that end up being wrong or unimportant – we’d soon be out of the game.

“I constantly worry that we’ve already made all the important discoveries we’re going to make, the challenge is to keep coming up with new ones.”

This feature appeared in the July/August 2009 issue of Australian Life Scientist. To subscribe to the magazine, go here.