Over the past 30 years, the United States has witnessed a substantial rise in the prevalence of obesity, amongst all population demographics. Many have attempted to tie this upsurge in cases as an indication of a failure in character or the lack of self-agency. These claims, however, are unsubstantiated. New research points to more nuanced molecular and neurobiological mechanisms, as well as environmental influences being responsible for the sudden rise in obesity rates.
A research team lead by Dr. Jennifer Beshel recently published the short article “A Leptin Analog Locally Produced in the Brain Acts via a Conserved Neural Circuit to Modulate Obesity-Linked Behaviors in Drosophila”, published in Cell Metabolism, where they discuss their findings of a homologous leptin pathway, in drosophila, to that found in mammals. More specifically the researchers characterize the relationship between the drosophila leptin analog, unpaired 1 (upd1), and the drosophila leptin receptor homolog, domeless receptors, as well as the NPY+ neuron homolog, NPF+ neurons. This pathway, as observed in mammals, involves the release of upd1 from adipose/upd1+ cells in the brain (as encoded by the OB gene), which can then bind onto and activate leptin receptors. This activates a signaling cascade that involves the dimerization of the leptin receptors, subsequent activation of JAK 2, phosphorylation of tyrosine residues on the cytoplasmic domain of the leptin receptor, which then allows STATs to bind, be phosphorylated to form a homodimer, and translocate to the nucleus where they will act as transcription factors to ultimately inhibit the activity of these NPY+ neurons, and as a result, inhibit feeding behaviors. This pathway is conserved in drosophila, so in an attempt to better understand how leptin could potentially affect obesity-related behavior, in humans, Beshel and her team produced a brain-specific knockout of upd1, to observe their behavior. What they noted in these knockout models was an increase in reactivity to odor cues, an increase in feeding, and a significant increase in weight, as compared to their wild-type counterparts. These same knockouts were then given a diet rich in fats and sugars and researchers observed that the flies became very large, very quickly. While upd1 knockout explains the weight increasing behavior, in the lab flies, this does not explain the sudden prevalence of obesity in humans. While some obesity cases (~5%) can be attributed to genetic mutations of the Ob/Db gene, most do not. This proves that disturbances in the upd1-NPF axis can lead to increased sensitivity to adverse, weight gaining environmental stressors, implying that this could potentially be the case in mammalian systems as well. It should be noted that in Beshel’s research she states that only knockout of upd1 in neurons increases weight gaining behavior, not upd1 knockout in adipocytes.
With a better understanding of the molecular mechanisms behind the leptin pathway, as well as its delicate homeostasis with environmental factors, we can fully appreciate the ease in which an organism can succumb to obesity and its damaging effects. As it so happens a recent study published in the Journal of Alzheimer’s Disease, “Patterns of Regional Cerebral Blood Flow as a Function of Obesity in Adults” highlights some of these catastrophic consequences. Daniel G. Amen et al. wanted to justify the claim that midlife obesity is a risk factor for the development of Alzheimer’s (AD). While the causes of AD are still being debated on, it is commonly known that AD is associated with the degeneration of several key cerebral areas such as the parietal/temporal lobes, hippocampus, posterior cingulate, and precuneus. Amen et al. proposed an experiment, in which they utilized brain SPECT imaging with technetium-99m hexamethyl propylene amine oxime to measure cerebral profusion of the previously stated brain areas, among underweight, normal weight, overweight, and obese patients. What they observed was that in all measured brain regions there was a decrease in perfusion as the weight category increased, while no regions showed elevated perfusion to be associated with elevated BMI. Furthermore, we should note that many of the research participants that were classified as obese also had psychiatric comorbidities; however, associated, partial correlation analyses illustrated that the presence of psychiatric disorders did not change the significant relationship between weight and cerebral perfusion. This is extremely noteworthy, as the results potentially allude to a relationship between the level of adipose tissue and potential development of AD, which is further explained by several molecular mechanisms, such as a neuroinflammation pathway involving the TREM-2 receptor.
Both Beshel et al. and Amen et al. aimed to gain a better understating of the sources of obesity and its consequences, respectfully. It should be noted that in Beshel’s research she discusses how the leptin receptor belongs to the IL-6 family. IL-6 has several isoforms, in which the soluble factor plays a crucial role in inflammation. It’s worth discussing that obesity is characterized as a state of systemic inflammation, relating to Amen’s discussion of the hypoperfusion of cerebral pathways that contain TREM-2 expressing cells, which inhibit inflammation. Could these two concepts be associated and potentially play a role in the associated markers of obesity, besides excessive adipose deposits? Whether or not this could be possible, both researchers have highlighted the complicated and dangerous nature of obesity. Further calling to attention the need for immediate action to reduce obesity rates to prevent increased biological sensitivity to obesity causing factors and by proxy associated cognitive disorders.
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