Researchers identified a brain enzyme that regulates how much food mice eat in one sitting—deletion of this enzyme caused the mice to increase their food intake to the point of becoming obese. The results could provide new therapeutic target for human obesity.
To study brain mechanisms that control meal size and thereby body weight, Olof Lagerlöf et al studied a pathway that has previously been associated with obesity. One enzyme in particular, O-GlcNAc transferase (OGT), which catalyzes the post-translational modification of proteins by O-GlcNAc, is regulated by nutrient access and interacts with insulin.
In the 18 March issue of Science, Lagerlöf et al report that when they knocked out OGT from calcium/calmodulin-dependent protein kinase II alpha (Camk2a)-positive neurons in adult mice, the mice developed obesity from overeating. Their daily food intake rapidly increased, plateauing at a level more than twice that of control mice. Within 3 weeks, the amount of fat tissue in the OGT-knockout mice tripled.
“These mice don’t understand that they’ve had enough food, so they keep eating,” said Lagerlöf in a press release.
The OGT-knockout mice ate larger meals, and for longer, with no change in meal frequency. This indicates that OGT signaling in brain neurons is required for satiation. If access to food was restricted to the same amount consumed by controls, the OGT-knockout mice retained normal body weight.
The effect of reduced OGT expression was most pronounced in neurons of the hypothalamic paraventricular nucleus (PVN)—a region associated with control of food intake and body weight (see figure).
Deletion of the gene encoding OGT specifically in Camk2a-expressing neurons in the PVN had the same effects as reducing expression in all Camk2a-expressing neurons in the brain, and was accompanied by massive body weight gain and hyperphagia associated with increased meal size.
Increased blood glucose concentration after feeding increased the expression of OGT and the transcription factor c-Fos (a marker of neuronal activation) in PVN Camk2a-positive neurons, whereas reduced OGT expression blocked c-Fos activation and reduced excitatory synaptic input to these neurons.
Lagerlöf et al examined the chemical and biological activity of the OGT-negative cells. By measuring the background electrical activity in non-firing brain cells, they estimated the number of incoming synapses on the cells and found that they were 3 times as few, compared to normal cells.
“That result suggests that, in these cells, OGT helps maintain synapses,” senior author Richard L. Huganir said in a press release. “The number of synapses on these cells was so low that they probably aren’t receiving enough input to fire. In turn, that suggests that these cells are responsible for sending the message to stop eating.”
Lagerlöf et al conclude that GlcN Acylation in Camk2a-positive neurons of the PVN is an important molecular mechanism that regulates feeding behavior.
“It’s very likely that the same mechanism and cell type in the brain are also found in humans. We think this type of appetite control mechanism probably occurs in humans, but we need to do more work to show that,” senior author Richard L. Huganir told The Independent.
“In theory, if we really understand what’s occurring here we might be able to deliberately target this mechanism with drugs that could control appetite, which could help in the fight against the obesity epidemic,” he said.
In an editorial that accompanied the article, Gary J Schwartz explains that in the central nervous system, nutrient sensors control the whole-body energy balance by modulating food intake. However, multiple hypothalamic and brainstem regions implicated in the control of food intake express OGT, including the hypothalamic arcuate, ventromedial, dorsomedial, and lateral hypothalamic nuclei, as well as the brainstem nucleus of the solitary tract and the parabrachial nucleus.
Schwartz says that the identification of nutritionally regulated OGT expression in multiple neuron populations that control feeding sets the stage for elucidating how the consequences of OGT nutrient sensing are coordinated to determine acute energy availability and long-term energy balance.