Listening to leptin: Researchers identify and block protein that interferes with appetite-suppressing hormone

Ever since the appetite-regulation hormone called leptin was discovered in 1994, scientists  have sought to understand the mechanisms that control its action. It was known that leptin was made by fat cells, reduced appetite and interacted with insulin , but the precise molecular details of its function —details that might enable the creation of a new treatment for obesity — remained elusive.

Now, University of Texas Medical Branch at Galveston researchers have revealed a significant part of one of those mechanisms, identifying a protein that can interfere with the brain’s response to leptin. They’ve also created a compound that blocks the protein’s action — a potential forerunner to an anti-obesity drug.

In experiments with mice fed a high-fat diet, scientists from UTMB and the University of California, San Diego explored the role of the protein, known as Epac1, in blocking leptin’s activity in the brain. They found that mice genetically engineered to be unable to produce Epac1 had lower body weights, lower body fat percentages, lower blood-plasma leptin levels and better glucose tolerance than normal mice.

When the researchers used a specially developed “Epac inhibitor” to treat brain-slice cultures taken from normal laboratory mice, they found elevated levels of proteins associated with greater leptin sensitivity. Similar results were seen in the genetically engineered mice that lacked the Epac1 gene. In addition, normal mice treated with the inhibitor had significantly lower levels of leptin in their blood plasma — an indication that Epac1 also affected their leptin levels.

“We found that we can increase leptin sensitivity by creating mice that lack the genes for Epac1 or through a pharmacological intervention with our Epac inhibitor,” said UTMB professor Xiaodong Cheng, lead author of a paper on the study that recently appeared on the cover of Molecular and Cellular Biology. “The knockout mice gave us a way to tease out the function of the protein, and the inhibitor served as a pharmacological probe that allowed us to manipulate these molecules in the cells.”

Cheng and his colleagues suspected a connection between Epac1 and leptin because Epac1 is activated by cyclic AMP, a signaling molecule linked to metabolism and leptin production and secretion. Cyclic AMP is tied to a multitude of other cell signaling processes, many of which are targeted by current drugs. Cheng believes that understanding how it acts through Epac1 (and another form of the protein called Epac2) will also generate new pharmaceutical possibilities — possibly including a drug therapy that will help fight obesity and diabetes.

“We refer to these Epac inhibitors as pharmacological probes, and while they are still far away from drugs, pharmaceutical intervention is always our eventual goal,” Cheng said. “We were the first to develop Epac inhibitors, and now we’re working very actively with Dr. Jia Zhou, a UTMB medicinal chemist, to modify them and improve their properties. In addition, we are collaborating with colleagues at the NIH National Center for Advancing Translational Sciences in searching for more potent and selective pharmacological probes for Epac proteins.”

Breakthrough in neuroscience could help re-wire appetite control

Researchers at the University of East Anglia (UEA) have made a discovery in neuroscience that could offer a long-lasting solution to eating disorders such as obesity.

It was previously thought that the nerve cells in the brain associated with appetite regulation were generated entirely during an embryo’s development in the womb and therefore their numbers were fixed for life.

But research published today in the Journal of Neuroscience has identified a population of stem cells capable of generating new appetite-regulating neurons in the brains of young and adult rodents.

Obesity has reached epidemic proportions globally. More than 1.4 billion adults worldwide are overweight and more than half a billion are obese. Associated health problems include type 2 diabetes, heart disease, arthritis and cancer. And at least 2.8 million people die each year as a result of being overweight or obese.

The economic burden on the NHS in the UK is estimated to be more than £5 billion annually. In the US, the healthcare cost tops $60 billion.

Scientists at UEA investigated the hypothalamus section of the brain – which regulates sleep and wake cycles, energy expenditure, appetite, thirst, hormone release and many other critical biological functions. The study looked specifically at the nerve cells that regulate appetite.

The researchers used ‘genetic fate mapping’ techniques to make their discovery – a method that tracks the development of stem cells and cells derived from them, at desired time points during the life of an animal.

They established that a population of brain cells called ‘tanycytes’ behave like stem cells and add new neurons to the appetite-regulating circuitry of the mouse brain after birth and into adulthood.

Lead researcher Dr Mohammad K. Hajihosseini, from UEA’s school of Biological Sciences, said: “Unlike dieting, translation of this discovery could eventually offer a permanent solution for tackling obesity.

“Loss or malfunctioning of neurons in the hypothalamus is the prime cause of eating disorders such as obesity.

“Until recently we thought that all of these nerve cells were generated during the embryonic period and so the circuitry that controls appetite was fixed.

“But this study has shown that the neural circuitry that controls appetite is not fixed in number and could possibly be manipulated numerically to tackle eating disorders.

“The next step is to define the group of genes and cellular processes that regulate the behaviour and activity of tanycytes. This information will further our understanding of brain stem cells and could be exploited to develop drugs that can modulate the number or functioning of appetite-regulating neurons.

“Our long-term goal of course is to translate this work to humans, which could take up to five or 10 years. It could lead to a permanent intervention in infancy for those predisposed to obesity, or later in life as the disease becomes apparent.”

Episodic Memory and Appetite Regulation in Humans

Psychological and neurobiological evidence implicates hippocampal-dependent memory processes in the control of hunger and food intake. In humans, these have been revealed in the hyperphagia that is associated with amnesia. However, it remains unclear whether ‘memory for recent eating’ plays a significant role in neurologically intact humans. In this study we isolated the extent to which memory for a recently consumed meal influences hunger and fullness over a three-hour period. Before lunch, half of our volunteers were shown 300 ml of soup and half were shown 500 ml. Orthogonal to this, half consumed 300 ml and half consumed 500 ml. This process yielded four separate groups (25 volunteers in each). Independent manipulation of the ‘actual’ and ‘perceived’ soup portion was achieved using a computer-controlled peristaltic pump. This was designed to either refill or draw soup from a soup bowl in a covert manner. Immediately after lunch, self-reported hunger was influenced by the actual and not the perceived amount of soup consumed. However, two and three hours after meal termination this pattern was reversed - hunger was predicted by the perceived amount and not the actual amount. Participants who thought they had consumed the larger 500-ml portion reported significantly less hunger. This was also associated with an increase in the ‘expected satiation’ of the soup 24-hours later. For the first time, this manipulation exposes the independent and important contribution of memory processes to satiety. Opportunities exist to capitalise on this finding to reduce energy intake in humans.