The mechanisms by which nutrient and hormonal signals regulate the storage and breakdown triglycerides and glycogen are still not completely understood. We are interested in the molecular mechanisms which control lipid and glycogen levels in muscle, liver and adipose tissue. We are particularly interested in the mechanisms by which insulin and amino acids modulate glycogen and lipid synthesis.
One of the pathways that lie at the intersection between nutrient levels and metabolic responses is the mTORC1 pathway. This protein kinase complex is regulated by a variety of anabolic signals including energy status (via AMPK), amino acids and growth factors such as insulin. mTORC1 can integrate these signals and alters metabolism to either store or use those nutrients. Some examples of mTORC1-dependent changes include:
- Promoting triglyceride and glycogen synthesis.
- mTORC1 can promote lipid synthesis by several mechanisms. These include regulating the transcription factors Lipin and SREBP1c. We have shown that SREBP is important for mTORC1 regulation of glycogen in the liver (see Lu et al.) and are investigating the role of the mTORC1/SREBP1c axis in adipose and muscle tissues as well)
- Altering energy utilization
- Another way by which mTORC1 can alter nutrient homeostasis is to promote nutrient utilization in energy consuming tissues. The up-regulation of metabolism is a normal response to energy excess, a process known as diet-induced thermogenesis. Several recent papers have shown that mTORC1 in muscle can increase energy expenditure, and we are investigating the mechanisms by which this happens as a way to promote negative energy balance.
- Generate new muscle and adipose tissue
- mTORC1 also plays an essential role in the formation of new muscle tissue (myogenesis) and adipocytes (adipogenesis). A recent paper from our group showed that this mechanism is conserved even in fruit flies (see Hatfield et al.)
To study this we are using a variety of mouse and cell culture models where we can test the effects of manipulating nutrient sensing pathways to determine the effects of these on glycogen and triglyceride storage.
Obesity, NAFLD Insulin resistance can be caused by several factors including obesity and inflammation. One of the more fascinating aspects of this physiology is how these phenotypes involve substantial communication between tissues, and the brain. We are working on how several hormones, including insulin and GDF15 communicate from the body the brain, and how other hormones under neuronal control (BDNF, cortisol and growth hormone) affect the periphery.
Pituitary tumors lead to over production of either growth hormone or cortisol, resulting in acromegaly and Cushing's Disease respectively. There is an incomplete understanding of the molecular mechanisms by which growth hormone and cortisol mediate insulin resistance and aberrant lipid metabolism in vivo.
To address this, in collaboration with groups at the Ramban Medical Institute in Haifa Israel, and the University of Michigan, we have performed an unbiased transcriptomic analysis of adipose tissue from human patients with acromegaly (see Hochberg et al., 2015 in PLOS One) or Cushing's disease (see Hochberg et al. 2015 in JME). We are using these data along with cell culture and mouse models to determine the mechanisms by which these endocrine diseases lead to altered metabolism.
Obesity as a Modifier of Glucocorticoid Signaling
There are several major effects of acute stress hormones including increased lipolysis, impaired insulin sensitivity, and muscle breakdown. Over the long run, chronic elevations in glucocorticoids can lead to increased adiposity and increased non-alcoholic fatty liver disease.
While evaluating transcriptional and physiological changes in glucocorticoid responses in adipose lysates from patients with Cushing's disease, we were surprised to find that obesity strongly promoted insulin resistance, NAFLD and the adipose transcriptome (see Hochberg et al. 2015).
To understand this further, we did several experiments where we generated lean and diet-induced obese mice and then gave them glucocorticoids, to ask whether the response was stronger in the obese mice. As we describe in Harvey et al., 2018 the mice with pre-existing obesity had dramatically worsened insulin sensitivity, fatty liver disease and lipolysis. We identified that in adipose tissue there was a strong up-regulation by obesity and glucocorticoids of the lipolytic enzyme ATGL, and elevated lipolysis. This suggested to us that adipose tissue is critical for these worsened metabolic responses. We are currently working to understand how obesity affects stress hormone signaling, and whether other effects of stress hormone signaling are affected by obesity. In terms of muscle function, we identified that obesity also increases dexamethasone-induced muscle atrophy and weakness, with a pronounced effect in type II muscle fibers (Gunder et al., 2020).
The Target of Rapamycin Complex I has been implicated in the regulation of aging and lifespan in many eukaryotic organisms ranging from yeast to humans. We are interested in how aberrant nutrient sensing, and TORC1 in specific, causes delayed or accelerated aging in model organisms.
To test this we are using mice, flies and yeast, we are studying how this complex is regulated during aging, and how manipulation of this complex alters lifespan and aging related phenotypes. We generate genetically modified or pharmacological approaches using these animals where these pathways are activated or repressed. We then test for changes in lifespan and normal function in these organisms. We are particularly interested in determining the molecular mechanisms and potential reversibility of these changes associated with aging.
The phosphatidylinositide lipid PI(3,5)P2 is synthesized by an enzyme named Pikfyve or Fab1 in eukaryotes. This enzyme is regulated by at least three conserved adaptor proteins, Vac14, Fig4 and Atg18. Having only been recently uncovered, the role of this enzyme and its lipid products is still under investigation.Recently we have observed that this lipid is synthesized in response to increased nutrient levels in mammalian cells. We also described a loss of mTORC1 function associated with decreases in PI(3,5)P2 levels. In collaboration with several investigators at the University of Michigan we have put forth the hypothesis that direct binding of the Raptor WD40 domain to PI(3,5)P2 is important for lipid regulation of this complex as far back as in budding yeast. Using newly generated genetic tools, we are examining the role of Pikfyve and its regulatory proteins in mice and yeast, focusing on the newly established role of this lipid in nutrient sensing.