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Leptin Resistance and Progressive Obesity Print E-mail
Living - Health & Fitness
TS-Si News Service   
Saturday, 15 October 2011 09:00
Leptin and Increased Fat Deposits.Melbourne, Victoria, Australia. New research shows how resistance to the hormone leptin, produced by the body in response to increasing fat deposits, can become a key causal component of obesity.

The health and monetary effects of obesity are well known, and now, scientists are getting closer to understanding how the disease progresses, providing clues for future treatments.


Ordinarily, leptin onstructs the brain's hypothalamus to increase energy expenditure and decrease food intake, enabling us to maintain a healthy body weight. However, lead author Tony Tiganis says that "The body's response to leptin is diminished in overweight and obese individuals, giving rise to the concept of leptin-resistance."

Tony Tiganis.

Tony Tiganis is a Professor at the Monash University Obesity and Diabetes Institute, Department of Biochemistry and Molecular Biology.

Professor Tiganis is focused on uncovering the pathways involved in human disease states, including obesity, diabetes and metabolic disorders.

"Simply telling people to eat less and exercise more is not going to be sufficient to reverse the obesity trend. There is a pressing need to develop novel drugs that complement diet and exercise to both prevent and treat this disease," says Tiganis.
In a study that appears in the journal Cell Metabolism, researchers at Monash University in collaboration with colleagues in the United States, have discovered more about how leptin-resistance develops, providing new directions for research into possible treatments."

Two proteins are already known to inhibit leptin in the brain and Professor Tiganis' team have discovered a third. In mice, this third protein becomes more abundant with weight-gain, exacerbating leptin-resistance and hastening progression to morbid obesity. The study showed that the three negative regulators of leptin take effect at different stages, shedding light on how obesity progresses.

"Drugs targeting one of the negative regulators are already in clinical trials for Type 2 Diabetes, however, our research shows that in terms of increasing leptin-sensitivity in obesity, targeting only one of these won't be enough. All three regulators might need to be switched off," said Professor Tiganis.

Leptin and fat development.The study showed that high fat diet-induced weight gain is largely prevented in genetically-modified mice when two of the negative regulators are deleted in the brain. "We now have to determine what happens when all three negative regulators are neutralised. Do we prevent high fat diet-induced obesity?"

Professor Tiganis said the more that is known about obesity, the better equipped scientists are to develop drugs to support good diet and exercise choices.

"Humans have a deep-seated attraction to overeating and nutrient-rich food, inherited from our hunter-gatherer ancestors. Now that food is more readily available and our lifestyles are less active, our evolutionary drive to overeat is becoming problematic."

More than four million Australians are obese and if current trends continue, by 2020, more than 80 per cent of adults and almost one third of children will be overweight or obese. Studies indicate that obesity and related health issues cost Australians more than $56 billion a year.

CitationElevated Hypothalamic TCPTP in Obesity Contributes to Cellular Leptin Resistance. Kim Loh, Atsushi Fukushima, Xinmei Zhang, Sandra Galic, Dana Briggs, Pablo J. Enriori, Stephanie Simonds, Florian Wiede, Alexander Reichenbach, Christine Hauser, Natalie A. Sims, Kendra K. Bence, Sheng Zhang, Zhong-Yin Zhang, Barbara B. Kahn, Benjamin G. Neel, Zane B. Andrews, Michael A. Cowley, and Tony Tiganis. Cell Metabolism 2011. doi:10.1016/j.cmet.2011.09.011

Highlights

●  Hypothalamic TCPTP is elevated in obesity together with PTP1B and SOCS3
●  TCPTP attenuates leptin-induced STAT3 signaling
●  TCPTP deficiency/inhibition enhances leptin sensitivity
●  Combined PTP1B/TCPTP deletion has additive effects on leptin sensitivity and obesity

Abstract

In obesity, anorectic responses to leptin are diminished, giving rise to the concept of “leptin resistance.” Increased expression of protein tyrosine phosphatase 1B (PTP1B) has been associated with the attenuation of leptin signaling and development of cellular leptin resistance. Here we report that hypothalamic levels of the tyrosine phosphatase TCPTP are also elevated in obesity to attenuate the leptin response. We show that mice that lack TCPTP in neuronal cells have enhanced leptin sensitivity and are resistant to high-fat-diet-induced weight gain and the development of leptin resistance. Also, intracerebroventricular administration of a TCPTP inhibitor enhances leptin signaling and responses in mice. Moreover, the combined deletion of TCPTP and PTP1B in neuronal cells has additive effects in the prevention of diet-induced obesity. Our results identify TCPTP as a critical negative regulator of hypothalamic leptin signaling and causally link elevated TCPTP to the development of cellular leptin resistance in obesity.

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Last Updated on Friday, 14 October 2011 22:41