Starving neurons of the hypothalamus appear to take a two-pronged approach to nutrient shortages: eat themselves in a process called autophagy as a short-term fix, and set off a cascade to make the organism crave more food, according to new research. The findings, published today (August 2) in Cell Metabolism, may explain why intense dieting can be so hard to stick with, and help scientists develop novel therapies to fight obesity, according to the study authors.
“The present study identifies the missing link [between the brain and weight control] as autophagy,” said Vojo Deretic, chair of the University of New Mexico’s department of molecular genetics and microbiology, who was not involved in the research. “It is definitely an interesting paper that may lead to bigger things in the future.”
Many people who try to diet simply can’t stick with the program, often driven by strong cravings for junk foods high in fat. Previous studies have demonstrated that increased levels of fatty acids floating extracellularly in the hypothalamus, a region of the brain that monitors nutritional status, triggers cravings. But the mechanisms that controlled the levels of these fatty molecules inside brain cells were unknown.
Molecular biologist Susmita Kaushik and her colleagues at the Albert Einstein College of Medicine in the Bronx, New York, decided to investigate one variety of hypothalamic neuron, the agouti-related peptide neuron (AgRP), whose activity has been linked to increased food intake. By removing nutrients supplies from the neurons in vitro and keeping food from mice, the researchers discovered that starvation activates autophagy—a common process involving the breakdown of a cell’s organelles and proteins. In essence, both in vitro and in the mice, AgRP neurons began to eat themselves, breaking down bits of fat droplets stored within their organelles and cytoplasm.
But as the stored fat gets chomped away, smaller fat molecules known as free fatty acids broke off and escaped into the extracellular space, which stimulated the production of more AgRP neurons and generated a hunger signal. So while the breakdown of the fatty acids served to provide the cells with energy during the period of low nutrients, the fatty leftovers were generating a feeling of hunger.
Kaushik and her colleagues then tested whether blocking autophagy in AgRP neurons would inhibit hunger. Mice lacking the autophagy gene atg7 in their hypothalamic neurons ate less food after fasting, and had higher levels of pro-opiomelanocortin (POMC), another hypothalamic neuron, and the hormone alpha-melanocyte (alpha-MSH), both of which typically suppress hunger and stimulate physical exercise. As a result, the knockout mice were leaner than their wildtype counterparts.
“The paper presents a new function of autophagy in AgRP-producing hypothalamic neurons in regulation of food intake and energy balance,” said co-author Rajat Singh of the Albert Einstein College of Medicine. “If therapeutic approaches were designed to control or decrease autophagy selectively in AgRP neurons, then these could potentially prevent obesity and diabetes.”
But Randy Seeley, a neuroscientist and director of the Cincinnati Diabetes and Obesity Center who was not involved in the research, isn’t convinced. “There are a number of significant challenges” before this knowledge can be translated into a treatment, he said. “Perhaps the biggest is that autophagy is a cellular process that happens in dang near every cell. There is no way to control the process in only AgRP neurons.”
Furthermore, the promise of a potential treatment is based on “the premise that autophagy is a free fatty acid generating process,” said Deretic—a finding that has come exclusively from studies conducted at Albert Einstein. “While there are several very strong papers on this topic, more work by independent groups may be needed to firm up the picture.”
“Nevertheless, the concept is tantalizing and exciting,” Deretic added. The findings “are a real fundamental advance in understanding autophagy” as it is related to starvation response in the brain, Seeley agreed.
S. Kaushik et al., “Autophagy in hypothalamic AgRP neurons regulates food intake and energy balance,” Cell Metabolism, DOI 10.1016/j.cmet.2011.06.008, 2011.