Dr Sandra Galic: targeting AMPK-ACC regulation to prevent rebound weight gain

Thursday, 8 Mar 2018

Challenge: can you describe the aim of this project in 10 words?
How does increased energy demand signal the need for compensatory energy intake?

What were some of your key findings?
The focus of this study was the enzyme AMP-activated protein kinase (AMPK), which is a well-known regulator of cellular energy metabolism. We found that under metabolic stress conditions, such as fasting or cold exposure, AMPK phosphorylates and inhibits the molecule acetyl-CoA carboxylase (ACC) to increase food intake and restore energy balance. Mice genetically modified to carry a mutated version of ACC that is unable to respond to AMPK control, are insensitive to the effects of the appetite-inducing hormone ghrelin. This hormone normally increases with fasting and has been previously linked to rebound weight gain after dieting. We therefore believe that we have found a crucial signalling mechanism, by which energy stress, such as encountered with weight loss and dieting, leads to compensatory increases in appetite. Pharmacologic inhibition of AMPK control of ACC may be a promising strategy to alleviate hunger associated with fasting by desensitising the body to the effects of ghrelin.

What aspect of this research excites you the most?
It was surprising that a small genetic mutation, as we have introduced in our genetically modified mice, has such profound effects on whole-body metabolism. A point mutation that specifically interferes with AMPK control of ACC, but leaves all other aspects of ACC regulation and function intact, was sufficient to affect a complex process, such as energy balance.

Does this represent a paradigm shift from the ‘energy in/energy out’ approach to weight control?
Unfortunately, the rule still applies that body weight gain or loss is a consequence of the long-term balance between energy intake and energy expenditure. Our research has merely provided another piece of the puzzle of how the body reacts to energy loss to restore energy balance. We are closer to understanding the compensatory actions that occur in response to weight loss and to identifying potential pharmacologic targets that may help prevent rebound weight gain.

What’s the next question to answer in this line of research?
Using mouse studies we are currently investigating whether inhibiting AMPK control of ACC is an effective long-term strategy for preventing rebound weight gain with calorie restriction. It is also important to establish whether this pathway regulates energy balance in response to other stress conditions, such as exercise, which is another common weight loss strategy.

How long before this work might impact clinical care?
The effectiveness of AMPK-ACC regulation as a long-term weight loss strategy will need to be confirmed in a pre-clinical setting. Furthermore, currently, there is no known drug capable of specifically targeting this pathway and if it existed, it would be very likely associated with some undesirable side effects in the liver, possibly promoting steatosis and increasing hepatic glucose output. It is therefore unlikely that we will see a clinical impact in the near future.

What’s your Holy Grail – the one thing you’d like to achieve in your research career?
To identify the molecular mechanisms of energy balance regulation, that may lead to novel therapeutic options for obesity treatment in everyday clinical practice.

What is your biggest research hurdle?
The current funding shortage and job insecurity in Australian medical research is an immense hurdle and makes it very difficult to commit to long-term studies required in energy metabolism research.

Who has inspired you in work or life?
There was not a single person, but rather the problem of obesity itself that inspired me. Overweight and obese people often face stigma and bias in everyday life, even by medical professionals. It is often overlooked that in response to weight loss the body undergoes chemical changes, such as reduced energy expenditure and increased appetite, that make it a very difficult uphill battle to achieve significant weight loss and maintain it. Finding a strategy to reduce these chemical barriers for effective weight loss could be of immense help for many overweight patients struggling with this problem.

How do you maintain work-life balance?
I often fail at maintaining a work-life balance, as the work as a scientist is frequently very challenging and time-intensive. It is not unusual to drop in on the weekends to complete experiments. It is probably balanced by the fact that I love science and I feel that the work itself can be immensely rewarding.

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