Numerous lines of evidence have suggested that energy balance in animals and humans is tightly controlled. With the identification of leptin and its receptors by our laboratory, two of the key molecular components of a system that maintains constant weight have been identified. Leptin is a hormone secreted by the adipose (fat) tissue in proportion to its mass that in turn modulates food intake relative to energy expenditure. Increased fat mass increases leptin levels, which in turn reduces body weight; decreased fat mass leads to a decrease in leptin levels and an increase in body weight. By this mechanism, weight is maintained within a relatively narrow range. Defects in the leptin gene are associated with severe obesity in animals and in humans. Leptin acts on sets of neurons in brain centers that control energy balance to regulate appetite. Leptin also plays a general role in regulating many of the physiologic responses that are observed with changes in nutritional state, with clear effects on female reproduction, immune function, and the function of many other hormones, including insulin. Recently, leptin was approved by the FDA for the treatment of severe lipodystrophy, a condition with extreme insulin resistance and diabetes resulting from a loss of fat tissue.
Our current research focuses on a series of questions pertinent to the regulation of body weight: How does the fat cell regulate how much leptin is made—i.e., how does the fat cell know how fat it is? How does a single molecule (leptin) change feeding, a complex behavior? How do brain pathways that are modulated by leptin in turn regulate peripheral metabolism and insulin action? Does variation in the genes that compose the physiologic circuit of which leptin is a component explain differences in body weight?
The Neural Circuitry Controlling Feeding
The recent identification of the hypothalamic cells that express the leptin receptor is enabling us to delineate the precise neuronal effects of leptin and the mechanisms by which this single molecule can alter a complex behavior. Recent studies have revealed that leptin reduces food intake by decreasing the hedonic value of nutrient i.e.; the pleasure associated with food. This is important because it shows that the pleasure we derive from eating is not fixed but rather reflects the status of metabolic signals such as leptin. We have also identified a specific neural population in the hypothalamus that expresses a bioactive peptide known as MCH as playing a key role in sensing the reward value of food. Ongoing studies seek to understand how leptin modulates the activity of these neurons. Several new methods have also been developed for identifying additional neural populations that regulate feeding. In the first, a novel gene profiling technology can be used to define neural populations whose activity are regulated by a stimulus. In the second, gene profiling technology is used to define specific neural populations based on their anatomic connections. (These latter two methods were developed from funds provided by a grant from the JPB Foundation.) Finally, we have developed a new method for probing neural function using magnets or radio waves to remotely modulate the activity of specific neural populations in vivo. The method is presented in a video below and enables one to noninvasively control neural activity remotely without the need for an implanted fiber. We are now using these methods to study neural pathways that control food intake and metabolism. We also plan to explore whether this method could provide a less invasive alternative to deep brain stimulation which is currently used to effectively treat a broad range of human diseases including Parkinson’s Disease. DBS however requires a permanent implant of an ~ 1 mm electrode into deep structures of the brain. (These studies are funded by a grant from the National Institutes of Health.)
Regulation of Leptin Production
We are also studying the molecular mechanisms responsible for changes of leptin gene expression associated with changes in fat mass (These studies were funded by a grant from the National Institutes of Health). The amount of leptin that is expressed from fat is strongly regulated, with a 100-fold or more level of expression from ob/ob adipose tissue than from the adipose tissue of a lean or fasted animal. This suggests that the fat cell knows how much fat they have and adjusts leptin expression accordingly. The underlying mechanism responsible for this regulation is unknown. To address this question, we are using transgenic mice to identify DNA regulatory elements that change expression of a reporter gene controlled by the leptin gene proportionately with changes in adipose tissue mass. We have thus modified a series of leptin bacterial artificial chromosome (BAC) clones so that the leptin DNA regulatory elements direct the expression of luciferase. This has enabled us to identify DNA regulatory sequences that control leptin gene expression. Protein factors binding to these sequences have also been identified and studies to elucidate how the activity of these factors changes, as fat is gained or lost are underway. We hypothesize that these studies will lead to the identification of a novel lipid sensing signaling pathway in adipocytes and possibly other cell types.
The Molecular Basis of Leptin's Metabolic Effects
Leptin has potent metabolic effects to improve insulin action and reduce the lipid content of peripheral tissues as retained and is now an FDA approved drug for the treatment of a sever form of human diabetes known as lipodystrophy. We are studying the mechanism responsible for leptin’s antidiabetic function in this and other forms of diabetes. Current data from our laboratory and others, suggest that leptin interferes with both the production and action of glucagon. Glucagon is another hormone that acts to increase blood glucose by opposing the effects of insulin. The cellular mechanisms responsible for this are under investigation.
Genetic Studies in Humans
Advances in genetics make it possible to use high throughput DNA sequencing to identify genes that contribute to human disease. To implement this approach, we have been conducting genetic studies in collaboration with Dr. Tayfun Ozcelik at Bilkent University in Ankara, Turkey. Genetic studies can be facilitated by studying patients who are children of first cousin (consanguineous) marriages which are very common in the Middle East. Dr. Dr. Ozcelik and his colleagues are collecting consanguineous pedigrees that include patients who are either morbidly obese, extremely lean or in other cases have Polycystic Ovary Disease (PCOS). PCOS is associated with extreme resistance to insulin. More than fifty such families have been collected thus far. Whole genome sequencing is now underway with the expectation that analyses of the DNA sequences from patients who are lean and obese will reveal DNA mutations that contribute to differences in weight, or, in other families, that lead to PCOS.
As of March 16, 2016