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Autophagy is a cellular recycling program that maintains quality control by degrading unwanted cytoplasmic contents in acidic organelles called lysosomes. Autophagy occurs at basal levels in all cells and is induced during starvation and stress. Autophagy requires greater than ~30 ATG proteins to orchestrate the de novo formation of a double-walled limiting membrane that sequesters cargo destined for degradation and seals upon itself to form an autophagosome. The delivery of the engulfed cargo to lysosomes by autophagosome-lysosome fusion results in cargo degradation.
Autophagy is a cellular recycling program that maintains quality control by degrading unwanted cytoplasmic contents in acidic organelles called lysosomes. Autophagy occurs at basal levels in all cells and is induced during starvation and stress. Autophagy requires greater than ~30 ATG proteins to orchestrate the de novo formation of a double-walled limiting membrane that sequesters cargo destined for degradation and seals upon itself to form an autophagosome. The delivery of the engulfed cargo to lysosomes by autophagosome-lysosome fusion results in cargo degradation.
We demonstrated a role for autophagy in the mobilization and degradation of intracellular lipid stores by a process we termed Lipophagy, thus mapping autophagy to metabolic regulation. Using live cell video-microscopy we found that smaller droplets are engulfed by autophagosomes in toto, while larger droplets are broken down piece meal. The sequestered lipid is delivered to lysosomes where lysosomal lipases generate free fatty acids that are released into the cytoplasm for their oxidation in mitochondria. Although lipophagy was initially described by us in liver and cultured cells (Nature, 2009), since then ~1500 articles have shown the existence of lipophagy in diverse cell types such as macrophages, neurons, foam cells, adipocytes and myocytes, to mention a few.
We have shown the Integrative role of hypothalamic autophagy in the regulation of feeding and peripheral metabolism. We have shown that lipophagy in hypothalamic neurons generates neuron-intrinsic free fatty acids that drive orexigenic AgRP expression and stimulate feeding. As a result, mice knocked-out for the autophagy gene Atg7 in AgRP neurons ate less and remained lean. By contrast, blocking autophagy in anorexigenic POMC neurons resulted in lower levels of neuronal alpha-MSH, hyperphagia, and obesity, suggesting a role for autophagy in the processing of POMC to alpha-MSH. Others have demonstrated that loss of autophagy results in reduced number and size of alpha-MSH-positive projections.
On similar lines, we have also shown that Autophagy in POMC neurons is required to stimulate autophagy and lipophagy in peripheral tissues, liver and brown fat. While knocking-out Atg7 in POMC neurons led to the blockage of lipophagy and accumulation of neutral lipid in liver and fat, stimulating autophagy in POMC neurons through intra-mediobasal hypothalamic injections of rapamycin led to stimulation of autophagy and rapid depletion of lipid in peripheral tissues.
More recently, we have demonstrated that Autophagy degrades the Clock repressor Cry1 to maintain glucose homeostasis. We have found that autophagy in liver is stimulated between 3pm and 7pm-which is when mice typically eat the least. During this time, the autophagy protein LC3 interacts with CRY1 via LC3-interacting region (LIR) motifs on CRY1. This results in the sequestration and degradation of CRY1. Under physiological states autophagy only degrades CRY1 and not Bmal1, Clock or Rev-Erb proteins. Given that CRY1 is a robust suppressor of gluconeogenesis, autophagic degradation of CRY1 allows gluconeogenesis to occur at maximal rates. On the basis of our studies, we are currently interested in developing drugs in collaboration with Dr. Evris Gavathiotis to prevent diabetes by interfering with LC3-CRY1 interaction, which will cause the stabilization of CRY1 such that gluconeogenesis is dampened and blood glucose levels are lowered.
The Focus of the laboratory is to examine the organ-specific roles of autophagy in the integrative regulation of lipid and energy metabolism using complementary approaches in mouse models. Our interests lie in understanding how autophagy controls energy, glucose, and lipid metabolism in a time-, diet-, and age-dependent manner. The Second Focus of the laboratory is to examine the consequences of aging-associated reduction of autophagy on the development of the metabolic syndrome. We are interested in understanding how autophagy decreases with age, and whether restoration of autophagy prevents the metabolic syndrome of aging. To that end, we have recently established an Isocaloric twice-a-day (ITAD) feeding intervention in mice that stimulates autophagy and prevents the metabolic syndrome of aging. Major benefits of ITAD feeding are - improved glucose tolerance, lower lipids levels, and increased muscle mass. Using different mice that lacked autophagy in POMC neurons or liver or fat tissue or myogenic progenitors, we have found that autophagy in different tissues contributes to distinct benefits of ITAD feeding. Given the positive outcomes of ITAD feeding in mice, we are currently collaborating with Dr. Jill Crandall (Division Chief, Endocrinology) to determine whether ITAD feeding will prevent the metabolic syndrome of aging by stimulating autophagy in human subjects.
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