FOEDRC research discover a new brain pathway that regulates body weight gain that is independent of the complications of obesity such as diabetes and high blood pressure
Obesity has reached epidemic proportions in the US and around the world. This is a problem because being obese increases the likelihood of developing serious medical problems such as type 2 diabetes, high blood pressure and cardiovascular diseases such as heart attacks and heart failure. Obesity also increases the risks of complications from COVID-19 infections. We still do not understand all of the reasons why obesity develops and why some people develop complications and others do not. In work recently published in the Journal Molecular Metabolism, FOEDRC member Dr. Kamal Rahmouni, PhD, professor of Neuroscience, Pharmacology, and Internal Medicine, in collaboration with FOEDRC colleagues at the University of Iowa, identified a protein complex, called the BBSome. These are present in neurons (nerve cells) in a part of the brain called the hypothalamus. The hypothalamus is a small area in the brain that determines whether the calories derived from the food we eat is burned or stored in the form of fat. The BBsome in these nerve cells regulate body fat and development of obesity. Dr. Rahmouni’s team found when the BBSome was removed from neurons of the hypothalamus, animals progressively increased body fat and weight resulting in obesity. This is due to inability of the hypothalamus to properly send signals to peripheral tissues that burn calories. As a result, these animals had lower metabolic rates as indicated by reduced energy expenditure. Because of this, their bodies were burning less calories than they should. Therefore, most of the ingested calories were directed to the fat tissues for storage, which increased the mass of fat tissue leading to obesity. These findings indicate that defects in the BBSome could be a potential cause of obesity. Very interestingly, the obesity that resulted from absence of the BBSome in the hypothalamus did not lead to diabetes, insulin resistance or high blood pressure. These findings are very similar to what is seen in a small subset of obese humans, referred to as “healthy obese,” who do not develop type 2 diabetes and cardiovascular diseases. The Rahmouni group is now conducting follow up studies to further understand what confers this remarkable protection against obesity-related conditions. Answering this question will reveal how metabolic and cardiovascular disease develop in obesity and may lead to more specific ways to treat these complications, particularly in individuals who struggle to lose weight.
Rouabhi M, Guo DF, Morgan DA, Zhu Z, López M, Zingman L, Grobe JL, Rahmouni K.. BBSome Ablation in SF1 Neurons Causes Obesity without the Comorbidities. Mol Metab. 2021 Mar 12:101211. doi: 10.1016/j.molmet.2021.101211. Epub ahead of print. PMID: 33722691.
FOE Investigators invited to educate the diabetes research community on new hormones from the liver that regulate metabolism.
FOEDRC member Matthew Potthoff, Ph.D., Associate Professor of Neuroscience and Pharmacology, and graduate student Sharon Jensen-Cody recently wrote a review article entitled: “Hepatokines and metabolism: Deciphering communication from the liver” that was published in the Journal Molecular Metabolism. This article was featured on the cover of the February issue of the Journal, that increased the visibility of their work. In that article Drs. Potthoff and Jensen-Cody note that the liver plays an important role in the regulation of the body’s energy metabolism. It is able to sense when nutrients are present in excess or are deficient. In response to these nutritional changes, the liver will release hormones that will instruct other tissues in the body how to respond. This means that the liver is now recognized as an endocrine organ (gland) that secretes hormones, which are now known as hepatokines. These liver-derived factors can signal to and communicate with distant tissues. In this review, Potthoff’s lab describe the growing list of hepatokines and their role in metabolic control. They also examine how each of these hepatokines function at the cellular and molecular level. They also discuss their potential to be used as as therapies for metabolic disorders such as diabetes and obesity. Dr. Potthoff’s laboratory in the FOEDRC has made major advances to this area of research, and his influence in this area is exemplified in this article.
FOEDRC Pioneering the Way
This month, the Spring 2021 issue of the Iowa Magazine devoted its cover and featured the University of Iowa Fraternal Order of Eagles Diabetes Research Center (FOEDRC). The heartwarming article shares real life testimonies of diabetic individuals, cared for at the University of Iowa and the impact of diabetes on their daily life. The desire for relief is real and certainly not lost on physicians and scientists at the FOEDRC. The Center’s mission is to improve the lives of individuals with the disease and find a cure. Every day dedicated FOEDRC scientists conduct a wide range of research projects to improve and benefit the lives of many.
In addition to featuring the work of specific FOEDRC members and highlighting the commitment of the FOEDRC to training the next generation of diabetes researchers, the article reminds us of the generous $25 million gift from the Fraternal Order of Eagles. Without the generosity of the Eagles, we would not have been able to make these wonderful strides in diabetes research. Thank you.
Below is the link to the Iowa Magazine article, I know you will enjoy reading it as much as I did.
FOEDRC Research Reveals New Mechanism for How Gastric Bypass Bariatric Surgery Promotes Weight Loss and Reverses Diabetes
The exact mechanisms underlying the metabolic effects of gastric bypass or bariatric surgery remain unclear. At the University of Iowa Carver College of Medicine, Mohamad Mokadem, MD, Assistant Professor of Internal Medicine and member of FOEDRC, and his research team have developed an animal model of bariatric surgery, which they are using to understand the underlying mechanisms by which this treatment not only prevents obesity but also reverses diabetes. Mokadem’s lab studied obese animals that underwent bariatric surgery (i.e. weight loss surgery) in order to understand the body’s physiologic response to such a treatment. Understanding these responses could lead to the development of similar therapies that are less invasive. They found that one type of bariatric surgery, namely the Roux-en-Y Gastric bypass, induces its weight loss and other metabolic benefits by altering the activity of a specific nerve (the splanchnic) that connects the gut to the brain to cause direct burning of the fat within the abdomen. This fat burning increases energy expenditure and is specific for this model of bariatric surgery. The new findings in their study identified a receptor within the intestine (the Endocannabinoid-receptor-1) that seems to be responsible for activating this “splanchnic” nerve signal to cause the metabolic benefits of this surgical procedure. The main implication of these findings on patient care is the future possibility of manipulating a specific receptor or its downstream effectors or the splanchnic nerve itself, to mimic the long-lasting effects of bariatric surgery. The more we understand details of how bariatric surgery works the more we will understand the underlying changes that are leading to the obesity epidemic. In addition, this research may lead to less invasive options to manage obesity and to reverse diabetes.
Too Much Sugar is Bad for the Heart
A recent study by a team of UI researchers led by E. Dale Abel, MD, PhD, Director, FOEDRC discovered eating a ketogenic diet rescued mice from heart failure.
The study, published in the November issue of the journal Nature Metabolism, was one of three companion papers from independent research teams that all point to the damaging effects of excess sugar (glucose) and its breakdown products on the heart. The UI study also revealed the potential to mitigate that damage by supplying the heart with alternate fuel sources in the form of high-fat diets.
Given its need for a constant, reliable supply of energy, the heart is very flexible about the type of molecules it can burn for fuel. Most of the heart’s energy comes from metabolizing fatty acids, but heart cells can also burn glucose and lactate, and also ketones.
Too much glucose, however, has been linked to heart failure, and heart failure is a leading cause of death in people with Type 2 diabetes. Heart biopsies from people with heart failure show an accumulation of sugar molecules in the heart, suggesting that this “backup” of glucose, because it is incompletely metabolized, may be contributing to the damage. The new UI study investigated how glucose and accumulation of these metabolites contribute to heart failure.
UI researchers removed a critical protein from heart cells in mice. This protein, called the pyruvate carrier protein, is responsible for taking pyruvate, derived from glucose metabolism, into mitochondria where it’s further metabolized to make energy. Levels of this protein are reduced in human failing hearts. Removing the pyruvate carrier protein prevents heart cells from using glucose as an energy source and causes a backup of the glucose-derived molecules, similar to what has been seen in human heart failure.
“We found that this was sufficient to cause these mouse hearts to fail,” Abel explains. “If you block this fundamental process of pyruvate uptake for energy, the unused glucose leaks into other metabolic pathways that lead to cell death and damage and contributes to heart failure. It’s really another way of saying that too much sugar is bad for the heart.”
There has been a long and controversial history of studies that counterintuitively suggest that high-fat diets may be beneficial to the heart. As this evidence has built up, there has been a growing interest in testing the effects of ketogenic diets in patients with heart failure, and several clinical trials are ongoing. The UI study used mice to investigate what happened when the mouse hearts that could not process glucose were provided with fats or ketones for energy instead.
The researchers found that ketogenic feeding (a high-fat, low-carbohydrate, low-protein diet) completely prevented heart failure and normalized heart function in diabetic mice. In addition, feeding the mice either ketones alone, or a high-fat diet that was not ketogenic, also rescued failing hearts.
Overall, the study suggested that shutting down the glucose overload by any means was beneficial.
“There’s something about too much glucose that appears to be very harmful,” says Abel.
The study doesn’t directly address whether this finding is relevant to heart failure in human patients, and if there are risks versus benefits to the heart of these high-fat diets. Abel says the study findings do not mean that patients with heart failure should start eating a keto diet.
“What I can say is that other studies have shown that when the heart begins to fail, it tends to want to use more ketones. So, it may be feasible that the heart uses ketones to try and rescue the failing heart,” he says. “Studies like ours really add impetus to the current clinical trials of ketogenic feeding in people with heart failure.”
Abel worked with a multidisciplinary team of UI researchers from the Fraternal Order of Eagles Diabetes Research Center and the Abboud Cardiovascular Research Center, as well colleagues from the University of Montreal in Canada, the University of Minnesota, the University of Utah, and The Ohio State University.
The research was funded in part by grants from the National Institutes of Health, the American Heart Association, the American Diabetes Association, and Montreal Heart Institute Foundation.