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Insights into How the Body Adjusts Its Thermostat To Regulate the Balance Between Food Intake and Calorie Burning

Researchers identified two factors that contribute to the critical balance of food intake and energy expenditure (calorie burning), in studies in mice. Mammals have precise and linked regulatory mechanisms to maintain body temperature and stabilize body weight. Food is converted to chemical energy, which the body uses, stores as fat, or converts to and dissipates as heat to adapt to various conditions (a process referred to as “adaptive thermogenesis”). The body can adjust its calorie burning, to some extent, based on the amount of food eaten. Decreased food intake leads to reduced energy expenditure, which limits weight loss. Conversely, increased food intake stimulates calorie-burning brown and beige fat cells to increase energy expenditure through the generation of heat (a form of adaptive thermogenesis referred to as “diet-induced thermogenesis”), limiting weight gain. When this regulation is disrupted, excess food intake and/or reduced energy expenditure can eventually lead to an increase in storage of the excess calories as fat, resulting in obesity. Scientists hope that, by understanding the body’s regulatory mechanisms, they can develop strategies to stimulate increased energy expenditure and to help combat the growing prevalence of obesity. Toward that goal, two studies from the same research group provided important insights into these regulatory mechanisms.

Previously the investigators demonstrated that a small molecule known as creatine enhanced energy expenditure. To explore the role of creatine specifically in adipose (fat) tissue, the researchers genetically engineered mice to lack a gene critical to the synthesis of creatine in fat cells and characterized the male mice. When these mice were transferred to a cold environment, the researchers observed that the mice lacking creatine in fat had reduced body temperatures, indicating that creatine plays a role in the production of heat to maintain body temperature. When the mice were fed a diet that can induce obesity, the researchers found that the mice lacking creatine in fat more rapidly developed obesity, compared to mice with creatine, and exhibited mild metabolic dysfunction, such as impaired glucose tolerance.

Importantly, both types of mice were eating the same amount of food and exhibiting similar levels of physical activity, so the scientists measured the resting energy expenditure in the mice to see if that would explain the acceleration of obesity and metabolic dysfunction. They found that, on the obesity-inducing diet, mice with creatine in their fat increased their energy expenditure and metabolic rate concomitantly to balance the extra calories. Mice lacking creatine in their fat, however, did not increase their energy expenditure and metabolic rate to the same extent; their diet-induced thermogenesis was suppressed. To determine whether this was specifically due to the loss of creatine, the scientists fed a creatine-supplemented diet to mice lacking creatine in their fat and observed that these mice showed an increase in metabolic rate, “rescuing” the loss of diet-induced thermogenesis. These results indicated that creatine in fat promotes diet-induced thermogenesis and combats obesity.

Equally important as the processes that promote thermogenesis are the processes that put a “brake” on thermogenesis, protecting animals from wasting energy by counterbalancing thermogenic processes. In a second study, the researchers identified a protein in fat, named KCNK3, that appears to act as this brake. Male and female mice genetically engineered to lack KCNK3 specifically in fat cells had increased body temperatures when placed in a cold environment compared to mice with KCNK3 in fat, indicating increased adaptive thermogenesis. When fed a diet that induces obesity, the genetically engineered mice gained significantly less weight than mice with KCNK3 in their fat cells and demonstrated increased energy expenditure. These mice also showed metabolic benefits, including improved glucose tolerance. Furthermore, the researchers demonstrated how KCNK3 activity leads to these outcomes: it increases the amount of potassium flowing out of a brown or beige fat cell, which limits the amount of calcium that can enter the cell; this process subsequently suppresses thermogenesis.

These two studies provide important details toward understanding the balance of energy intake and expenditure in mammals, and identify two new potential therapeutic targets in brown and beige fat for treatment of obesity and type 2 diabetes. As both these studies were conducted in mice, additional research will be necessary to determine the roles that creatine and KCNK3 play in human energy metabolism, and if creatine supplementation and/or KCNK3 antagonists can promote energy expenditure in humans.

References

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