Satchidananda Panda

Satchidananda Panda (born in 1971) is an Indian chronobiologist who currently works as a Professor at the Salk Institute for Biological Studies. He has made several notable contributions to the field of chronobiology. He established that melanopsin and intrinsically photosensitive retinal ganglion cells (ipRGCs) play a dominant role in circadian photoentrainment. He also conducted research on time-restricted feeding (TRF). Currently, through explorations of the circadian rhythmicity of metabolism in mice, Panda and his lab have research that they believe may prevent obesity through the timing of eating.

Academic Career

Panda was born and raised in India. Here, Panda earned his bachelor’s degree in agriculture, specializing in genetics and plant breeding, from Orissa University of Agriculture and Technology in 1991. Afterwards, he pursued a master's program in biotechnology at Tamilnadu Agricultural University and graduated in 1994. Panda then decided to move to the United States and joined the graduate program at The Scripps Research Institute where he studied the circadian oscillator mechanism in plants under Dr. Steve Kay. Since receiving his PhD in 2011, he conducted postdoctoral research in Dr. John Hogenesch’s lab at the Genomics Institute of the Novartis Research Foundation in San Diego. Here, he tried to understand the light input pathway along with circadian regulation of behavior and physiology in mammals by using genetic and genomic approaches. His work revealed tissue-specific circadian regulation of transcription and suggested that mammals engage multiple photoreceptors to adapt to their natural environment.

Research

Melanopsin Receptors

One of the main focuses of Panda’s lab is circadian photoentrainment in mammals, specifically the role of melanopsin in circadian photoentrainment.

In 2002, Panda generated a line of melanopsin knockout (Opn4) mice using homologous recombination in mice embryonic stem cells to replacing the first exon of the melanopsin gene with a neomycin-resistant gene. Panda placed these mice in two different environments: a normal photoperiod using 480 nm light and constant darkness, and observed their subsequent behavior. Panda's results showed that these mice were still able to entrain to the photoperiod. However, melanopsin KO mice showed attenuated entrainment capabilities compared to wild type (WT) mice with a shift magnitude about half of the WT mice. Panda then exposed the melanopsin KO mice to the same wavelength as before but with varying light intensities. He found that lower intensities produced the greatest entrainment differences between both mouse lines.

In constant darkness, melanopsin KO mice free-ran properly, displaying no difference from WT mice. Panda then placed these mice in constant white light and observed a similar trend. Melanopsin KO mice displayed the expected circadian period lengthening, but not with the same magnitude as WT mice.

This research concluded that melanopsin does play a role in photoentrainment process, though it is not necessary. However, despite its role in photoentrainment, melanopsin does not seem directly involved in core circadian clock functions as the melanopsin KO mouse line did not display any observable changes in circadian activity rhythms.

In 2003, Panda crossed a melanopsin KO mouse line (Opn4−/−) with a mouse line (rd/rd) lacking rods and cones in the retina. This generated a new mouse line which lacked both melanopsin and functional rods and cones. Using this line, Panda exposed mice to constant light and constant dark environments as well as normal photoperiods, similar to his 2002 experiment. Melanopsin KO mice lacking both rods and cones free ran in constant dark environments, mirroring the response of mice lacking only melanopsin. However, in constant light environments and normal photoperiods, mice lacking both melanopsin and functioning rods and cones free ran as well. There was no observable attempt to entrain the the cycle. Thus, mice do not contain any other photoreceptor that is sufficient to induce photoentrainment. However, rods and cones or melanopsin alone is sufficient for photoentrainment.

In 2008, Panda and colleagues published their findings regarding inducible ablation of melanopsin-expressing retinal ganglion. These scientists found that melanopsin-expressing retinal ganglion cells (mRGCs) integrate rod/cone and melanopsin phototransduction pathways. They also determined that these ganglion cells begin to separate image-forming and non-image forming photoresponses in mammals. This experiment was conducted by genetically labeling mRGCs in mice to discover that only a subset of these ganglion cells express enough immunocytochemically detectable levels of melanopsin. Additionally they expressed the diphtheria toxin receptor (DTR) in mRGCs. Diphtheria toxin administration can stunt normal mRGC development but mRGC-ablated mice still have normal outer retinal function.

Molecular Mechanism of Mammalian Circadian Rhythm

A large portion of Panda’s work as a chronobiologist has focused on using mouse models to create a better understanding of the molecular mechanism behind mammalian circadian rhythm. While there is well-documented evidence that biological processes such as metabolism and autophagy are under circadian control, Panda seeks to further explore the mechanisms and Transcription Translation (Negative) Feedback Loops (TTFL) that regulate these processes. Panda’s lab uses genetics and genomics to identify various genes under circadian control and then uses biochemical techniques to see how this circadian control is carried out. For example, when examining the transcription of the Clock and Bmal1 transcription factors within mouse liver, Panda discovered a histone lysine demethylase 1a (JARID1a) that enhances Clock-Bmal1 transcription. Without JARID1a, the period of the circadian rhythm is shortened and Per expression is lowered, thus showcasing its key role in proper circadian oscillation. Panda focused on developing a model for how JARID1a works to moderate the level of Per transcription by regulating the transition between its repression and activation.

Much of Panda’s work about metabolism has centered on gluconeogenesis and glucose homeostasis, with implications for better understanding the importance of the timing of eating. For instance, Panda found that the circadian clock protein Cryptochrome regulates gluconeogenesis in the liver. Typical of his work, Panda focused on the mechanism through which this regulation occurs and discovered that a fasting signal created when glucagon binds to a G-protein coupled receptor (GPCR) which triggers CREB phosphorylation activates the cAMP/CREB signaling that leads to gluconeogenesis, and Crytochrome inhibits this cAMP signaling and production. Therefore, the rhythmicity of Cryptochrome shapes how the mammalian body responds to fasting at different times in the day.  In addition, other clock proteins such as Bmal1 and Clock regulate glucose homeostasis. Without Bmal1 and Clock, the rhythmicity of glucose and triglyercerides is lost and gluconeogensis is respectively abolished or depressed. In fact, Bmal1 and Clock have been found to play a role in the recovery from insulin-induced hypoglycaemia.

Time Restricted Feeding (TRF)

One area of Panda’s research focuses on eating patterns and its significant effect on physiology; specifically time-restricted-feeding (TRF), which only allows the animal of interest to eat during a defined period of time, from dusk to dawn in mice. TRF does not restrict caloric intake but rather only limits when food is available. His findings from these experiments have implications on humans as well, particularly relating to eating disorders.

In 2014, Panda and his team wanted to test whether obesity and other metabolic diseases are a direct result from an increased caloric intake from a high fat diet (HFD) or disruption to normal feeding cycle caused by eating frequently throughout day and night (ad lib). They subjected mice to two conditions: eating a HFD but either on a TRF schedule or ad lib. From this, they found that mice eating a HFD of equivalent caloric intake to that of their ad lib counterparts were protected against obesity, hyperinsulinemia, hepatic steatosis, inflammation and have improved motor coordination. The TRF diet was found to enhance CREB, mTOR and AMPK pathway function as well as the oscillations of the circadian clock and their target genes’ expression. Additionally, the TRF diet stabilized and even reversed the progression of metabolic diseases in mice with pre-existing obesity and type II diabetes.

In 2015, Panda and his team performed tests involving his TRF diet in drosophila. They found similar results as before in that those under TRF had improved sleep (TRF flies were more active during the daytime) and prevention of body weight gain. Additionally, they also found that these results correlated with improvements in cardiac function of Drosophila. To do this, they measured the diameter of the beating Drosophila heart at full relaxation and contraction as well as the time interval between successive contractions to measure cardiac function parameters. These cardiac performance parameters - heart period (HP), systolic diameter (SD), systolic interval (SI), diastolic diameter (DD), and diastolic interval (DI), arrhythmia index (AI), and heart contractility - all showed smaller changes in TRF flies than that of their ad lib counterparts.

Panda created a smartphone app that monitored ingestion events in healthy adults. They found that most subjects ate frequently and erratically throughout the day and their nighttime fasting duration equaled the amount of time in bed. Additionally, the app showed that most people consumed their calories late at night (>35% after 6pm vs <25% before noon). These subjects have a “metabolic jetlag” due to the discrepancies between their weekday vs workday eating patterns. In a new experiment, Panda put overweight individuals that consumed calories >14 hours in a single day on a TRF diet for only 10-11 hours daily. After 16 weeks, subjects had reduced body weight, more energy and improved sleep.

Selected Publications

• Melanopsin (Opn4) requirement for normal light-induced circadian phase shifting (2002)
• Coordinated transcription of key pathways in the mouse by the circadian clock (2002)
• Melanopsin Is Required for Non-Image-Forming Photic Responses in Blind Mice (2003)
• Illumination of the melanopsin signaling pathway (2005)
• Role of novel photopigment, melanopsin, in behavioral adaption to light (2007)
• CRY links the circadian clock and CREB-mediated gluconeogenesis (2010)
• Histone lysine demethylase JARID1a activates CLOCK-BMAL1 and influences the circadian clock (2011)

Awards

2003 Finalist for Science-Eppendorf Prize in Neurobiology.

2006 Dana Foundation award in brain and immune system imaging

2006 Pew Scholar in Biomedical Research

2006 Whitehall Foundation Junior faculty award

2014 The Julie Martin Mid-Career Award in Aging Research

References

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