A noticeable impact on the waistline of many people is a side-effect of the quarantine due to the global COVID-19 outbreak. Reduced activity and lack of sports while consuming the same, or even elevated amounts of calories can quickly cause a substantial weight gain. Strikingly, some individuals can make it through this period without gaining any weight – we all know people who can eat what they want but do not appear to gain weight. A consortium of international researchers including scientists from IMBA, the University of British Columbia, Medical University of Vienna, and the Estonian Biobank have now taken a unique approach: thus far, the regulation of fat metabolism has mainly focused on finding genes linked to obesity. The team, however, went on a quest to discover genes linked to thinness, or the resistance to weight gain.
How do people, flies and mice stay thin?
In order to identify candidate thinness genes, the research team conducted genome-wide association studies in an Estonian population cohort, profiling over 47000 people. They compared thin to control individuals and were thereby able to pinpoint ALK, which codes for Anaplastic Lymphoma Kinase, as a candidate gene for thinness. ALK was mainly known due to its involvement in cancer, as it is frequently mutated in multiple cancers. However, its physiological function was largely elusive.
To test the hypothesis of ALK being involved in thinness, the researchers inactivated the Alk gene in mice. Strikingly, despite normal food intake and activity, Alk deficient mice were skinnier because of a much-reduced fat mass and strikingly protected against diet-induced obesity as opposed to littermate controls. Interestingly, when knocking down the ALK orthologues in the fruit fly Drosophila melanogaster, they also found significantly lower triglyceride fat accumulation, even when flies were fed a high-sucrose diet.
First author Michael Orthofer from the Penninger lab explains that Alk deficient mice exhibit increased energy expenditure. This means that they burn more calories than normal mice and explains why they remain thin even if they eat the same amount of food. In addition to that, these animals also show improved glucose tolerance.
Weight reduction starts in your brain
ALK is highest expressed in a very specific brain region called the paraventricular nucleus (PVN) of the hypothalamus. When the scientists depleted Alk in this brain area, a similar body weight reduction was observed compared to full-body Alk knockout models. The PVN is known to be involved in the regulation of energy homeostasis, both via hormonal pathways and the sympathetic nervous system, which uses norepinephrine as neurotransmitter. Indeed, levels of the neurotransmitter norepinephrine were elevated in both white and brown fat of the mutant mice, indicating that ALK deficiency increases sympathetic tone to adipose tissues. Consequently, Alk knockout mice showed increased breakdown of fat, which explains their low body adiposity and resistance to weight gain.
“This strengthens the notion that ALK is indeed part of a larger brain circuit involved in energy expenditure. We are very excited about these results on the genetics of thinness and will further investigate the mechanisms of how ALK-expressing neurons are able to control weight. Our results also highlight the important therapeutic potential of ALK inhibition,” says Josef Penninger, IMBA group leader and founding director, who is now director of the Life Sciences Institute of the University of British Columbia.