Fat cells secrete hormones that impinge on neural circuits to regulate hunger, exercise, reproduction and immunity. We study how fat hormones -adipokines- control physiology in healthy and dysfunctional states. By revealing how fat stores impact cognition, behavior and immunity, our findings will inform the development of therapies that target obesity.

Taking advantage of the deep, and unexpected, evolutionary conservation between fat-brain communication in flies and humans (Rajan and Perrimon, Cell, 2012) , we explore how adipokine (fat hormone) signaling modulates many aspects of physiology.

By investigating fat physiology, we have uncovered new insights in the areas of:

1. of cell biology, we discovered a mechanism by which fat cells couple nutrient state to secretion (Rajan et al., Dev Cell, 2017)

2. and neurobiology by uncovering how two hormones act on the same synapse to regulate its structure and shown that this mechanism regulates body-weight (Brent and Rajan., Cell Metabolism, 2020).

SOME OF THE SPECIFIC QUESTIONS THAT WE ARE ACTIVELY INVESTIGATING:

1.   Mechanisms regulating nutrient-dependent protein localization in fat cells.

2.   How does adipokine nuclear accumulation regulate post-feeding hunger motivation?

3.   Modulators and regulators of adipokine transit across the blood-brain barrier.

4.   Whether and how a metabolically dysfunctional state causes cognitive decline.  

5.   Dissect how fat stores influence innate immune system activity during infections.

Approach:

To address these questions, we deploy an inter-disciplinary toolkit, both in vivo and using cell culture-based systems. Techniques we use regularly are fruit fly genetics, behavioral assays, quantitative imaging, lipid chromatography, mass spectrometry etc., in conjunction with emerging approaches including super resolution microscopy and cutting-edge methods in genomics and proteomics.

Collectively, our investigations will illuminate how unhealthy levels of body fat deregulates cognition and immunity, thus affecting fitness.

WHY WE USE FRUIT FLIES TO INVESTIGATE FAT-BRAIN COMMUNICATION?

Obesity is a result of dysfunctional energy homeostasis. Energy homeostasis enables maintenance of metabolic parameters, such as blood glucose and fat stores, within a permissible range. Maintenance of homeostasis requires communication between organs that sense nutritional status and those which integrate and respond to signals from sensors. A key ‘sensor’ of energy is the adipose tissue, which is composed of fat cells/adipocytes. Adipocytes communicate the total stored energy by secreting factors called adipokines. Adipokines signal to neural circuits in the central nervous system (CNS) that regulate food intake and energy expenditure, serving as ‘responders’ in the homeostatic loop.

Leptin is a primary adipokine that is released in proportion to the fat stores and impinges on CNS to regulate energy expenditure, appetite and physiological processes such as reproduction and immunity that occur only in high nutrition environments [you can learn more about this hormone and fat by listening to this NPR segment (click link)]. Improper Leptin signaling occurs in obese individuals. It is unclear why Leptin fails to signal effectively as fat stores increase. 

We found that the hormone used by fruit flies to communicate information regarding its fat stores to its central nervous system is the same one humans (click link). Fruit flies are a premier model system with a wealth of techniques- from state-of-art genetic tricks to biochemical assays, and superb imaging tools including high resolution quantitative imaging. Using this model system, we will define how Leptin signaling works during 'normal' states. Then address how dysfunctional Leptin signaling occurs during chronic nutritional overload. Our ultimate goal is to understand how surplus signaling fails during 'over-nutrition'.

RELEVANT PUBLICATIONS: See PUBLICATIONS TAB

FUNDING:

Our work is funded by the National Institutes of Health.

NIDDK: R00 DK101605 &  NIGMS: R35 GM124593