Abstract
Obesity is the result of a long-term positive energy balance in which caloric intake overrides energy expenditure. This anabolic state results from the defective activity of hypothalamic neurons involved in the sensing and response to adiposity. However, it is currently unknown what the earliest obesity-linked hypothalamic defect is and how it orchestrates the energy imbalance present in obesity. Using an outbred model of diet-induced obesity we show that defective regulation of hypothalamic POMC is the earliest marker distinguishing obesity-prone from obesity-resistant mice. The early inhibition of hypothalamic POMC was sufficient to transform obesity-resistant in obesity-prone mice. In addition, the post-prandial change in the blood level of β-endorphin, a POMC-derived peptide, correlates with body mass gain in rodents and humans. Taken together, these results suggest that defective regulation of POMC expression, which leads to a change of β-endorphin levels, is the earliest hypothalamic defect leading to obesity.
Highlights
Increased consumption of dietary fats is one of the leading causes of obesity, which affects, currently, more than 500 million people around the world[1,2]
These results suggest that distinction in body mass between the groups is a result of increased caloric intake during the first four weeks
The hypothalamus has an important role in the regulation of whole body energy stores and early defects in its function may impact on the genesis of obesity[15,16]
Summary
Increased consumption of dietary fats is one of the leading causes of obesity, which affects, currently, more than 500 million people around the world[1,2]. Recent studies have shown that dietary fats promote obesity because of their caloric value and because they can damage the hypothalamic neuronal circuitries that control whole body energy homeostasis[3,4,5,6]. To human populations, outbred strains of rodents can present some degree of protection against obesity when exposed to unlimited amounts of dietary fats[10]. When exposed to unlimited amounts of dietary fat, approximately 50% of the animals become obese and diabetic[12,13]. In the present study we developed a strategy to identify the 25% of animals with the highest predisposition to or highest protection against obesity. We show that the anomalous regulation of hypothalamic POMC precedes inflammation and is a determining factor leading to the progression of obesity. In rodents and humans, blood levels of β-endorphin, a subproduct of the POMC transcript, is regulated differently in obesity-prone and obesity-resistant subjects
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
