Research

Learn more about the Mulholland Lab's work and impact.

Dr. Mulholland and Dr. Zhang in the lab with a team member
Lab member
Dr. Zhang

Mulholland Lab Overview

Obesity occurs when energy intake exceeds energy expenditure; at the physiologic level, it's a disorder of energy imbalance. Energy, that is food, intake is largely regulated by the central nervous system, particularly the hypothalamus.

Our laboratory investigates the molecular and genetic underpinnings of energy homeostasis. We focus on two key hypothalamic hormones, proopiomelanocortin (POMC) and neuropeptide Y and the mechanisms that regulate them.

Strategies

The POMC – neuropeptide Y system and its role in energy homeostasis has been known for quite some time. Our laboratory has been interested in its regulation, and many of our investigations explore the factors that tip the energy balance.

More specifically, we look at a receptor we recently identified as part of a regulatory system for the POMC – neuropeptide Y balance over the long term, leucine-rich repeat-containing and G-protein-coupled receptor 4 (LGR4), and its ligand, R-spondin 1. The LGR4 – R-spondin 1 system functions much like a thermostat that controls temperature in a building. The system also acts upon the hormone leptin to "set" the body's point of energy equilibrium. In addition, our work looks at the LGR4 – R-spondin system and its influence on fat deposition in liver cells, known as nonalcoholic fatty liver disease, which can lead to cirrhosis and long-term organ injury.

Results

Our work has elucidated the relationship between the gastric fuel-sensing protein mammalian target of rapamycin (mTOR) and ghrelin, the so-called "hunger hormone," as well as the ways in which ghrelin and the hormone nesfatin-1 work together to regulate energy balance.

Through further work on mTOR and the ghrelin- nesfatin-1 balance, we have shown that these hormones, controlled by mTOR signaling, regulate how lipids are metabolized and stored in the liver. The findings are of particular interest with respect to potential new therapeutic approaches to treating nonalcoholic fatty liver disease.

More recently, we have shown for the first time how a system that regulates two key hypothalamic hormones — proopiomelanocortin (POMC) and neuropeptide Y — works to control energy balance over time. The system is comprised of leucine-rich repeat-containing and G-protein-coupled receptor 4 (LGR4) and its ligand, R-spondin 1.

Clinical Relevance & Impact

The basic science research conducted in our laboratory into the mechanisms underlying energy homeostasis is advancing the understanding of how overweight and obesity, and their sequelae in the liver, develop. Knowledge of the mechanisms and pathways involved will ultimately lead to new approaches to treatment and prevention of obesity, thereby reducing its burden.

Future Directions

Using a combination of multiple cellular and molecular approaches, we are characterizing novel secreting molecules from the gut and exploring their actions on the energy homeostasis. In particular, we aim to define the novel gut-liver and gut-hypothalamus crosstalk.

Collaborations

Our lab collaborates with Randy Seeley, PhD, the Henry King Ransom Endowed Professor of Surgery, and Darleen Sandoval, PhD. They are the principal investigators of the Seeley & Sandoval Lab in the Department of Surgery, and Dr. Seeley is the director of the Michigan Nutrition Obesity Research Center (MNORC) at the University of Michigan.

 

  • National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) R01: R-spondin1-LGR4 signaling and ischemia/reperfusion injury in steatotic liver
  • NIH NIDDK R01: Gastric X/A Like Cells in Health and Diseases