The blood-brain barrier (BBB) is an important physiological formation tasked with protecting the brain from multiple chemicals that might circulate in our bloodstream. The BBB obstructs the exchange and movement of most molecules, cells, and proteins in and out of the central nervous system (CNS). This helps to keep the brain “cool” and unaffected by whatever we eat and the kind of infections we encounter. The BBB is formed by the blood vessels in the CNS that are lined by endothelial cells. It is a complex structure that ensures the maintenance of the metabolic and immunoregulatory homeostasis in the CNS. In a healthy brain, the barrier prevents most of the cerebrospinal fluid (CSF) molecules from circulating in the periphery and most of the peripheral molecules from diffusing into the CSF.

However, even in healthy brains, the BBB is not completely impermeable. The arcuate nucleus of the hypothalamus has an incomplete BBB, allowing circulating hormones to act on the regulatory systems of this part of the brain. Several neurological disorders are characterized by a compromised BBB, including stroke, CNS infections, and neurodegenerative diseases.

Obesity and BBB

It has been shown that overconsumption of foods high in saturated fats and simple sugars degrades the integrity of the BBB and could lead to the serious damage of vulnerable brain regions such as the hippocampus. Moreover, obesity causes pathological changes to the BBB that can worsen one’s general health and lead to additional pathological changes in the CNS such as neuroinflammation and cognitive decline. Obesity also causes changes to the number of cell types in a neurovascular unit that alters the BBB integrity.

However, in most overweight people, the excess body weight does not stimulate serious pathological processes. Obesity is not exactly a disorder that damages the brain, and the integrity of the BBB is not compromised by excess body weight. However, there is a remarkable link between obesity and the BBB, and this link exists because of how the brain functions normally.

Brain systems regulating feeding behavior

The systems involved in the development of obesity are complex and still not fully understood. However, it is believed that a disrupted energy homeostasis could be the root of the problem. Feeding behavior is regulated by metabolic, autonomic, endocrine, and environmental factors. Although it is influenced by numerous elements in each individual, “energy homeostasis” plays an important role by creating a balance between energy intake and expenditure.

The hypothalamus is one of the brain areas that has been recognized as a regulator of food intake, body weight, energy, and glucose homeostasis. It receives and processes the metabolic signal from the periphery, and reward and sensory inputs from the cortex. In turn, it sends output signals to the parts of central nervous system regulating feeding behavior and body weight.

Feeding hormones and the role of leptin

The hypothalamus is involved in the regulation of appetite through one appetite-stimulating signaling pathway and one appetite-suppressing pathway. These pathways involve specific hormones and neuropeptides, that can be found either in the blood or the CSF. In order for these hormones to function properly, they have to cross the vascular BBB via specialized transport systems. Many of the hormones regulating feeding behavior are disrupted in obesity, including insulin, leptin, adiponectin, and ghrelin.

One of the key hormones in the development of obesity is leptin. Leptin participates in energy homeostasis and regulation of metabolism. It responds to the satiety signals produced during food consumption. Leptin is secreted by the adipose tissue, and its secretion is positively correlated with the amount of body fat. Its secretion sends signals to the brain to suppress appetite and increase thermogenesis, in an attempt to decrease adiposity. As the body fat rises, the blood leptin levels increase. During periods of fasting when body weight drops, the secretion of leptin is decreased. In general, it has been shown that blood leptin concentration is significantly higher in obese people compared to leaner individuals, and this elevated level is decreased when obese people lose weight. It would be logical to assume that with a high level of leptin in the bloodstream, obese individuals should feel satiated. However, this is not the case. The levels of leptin in the blood are not reflecting the levels of leptin in the CSF. It has been shown that the ratio of CSF-to-serum leptin levels was four times lower in obese individuals.

Leptin resistance

This nonlinear correlation between the concentration of leptin in the blood and the CSF could be due to the so-called central resistance to leptin action. The theory of leptin’s central resistance suggests that obesity could be caused by the restricted access of leptin to the brain. This contrasts with older suggestions that obesity could be caused by an inadequate production of leptin.

An important factor to consider is that the transportation of leptin from blood circulation to the brain through the BBB is achieved via specialized transporter proteins that are prone to saturation. This means that the level of transporters is not high enough to transport enough leptin molecules into the brain. This is a classical “traffic jam” situation: only a certain amount of cars can come through the road bottleneck, regardless of how many cars are in the queue. As a result, the brain doesn’t “feel” the real concentration of leptin in the blood. Due to saturation of this transport through the BBB, the circulating levels of leptin do not always correspond to the CSF concentration of leptin. It has been suggested that this transport system functions similarly in lean individuals with normal leptin concentrations and that the higher leptin levels have no biological effects once the system is already saturated. The brains of obese hyperleptinemic subjects are not even exposed to the elevated levels of leptin.

Can the BBB cause obesity?

The fact that the transport system is also saturated in lean individuals shows that the BBB’s leptin transport system has evolved to properly function only at lower adiposity and body weight. Low levels of serum leptin inform the brain that adipose reserves are adequate to expend calories on functions other than feeding, such as reproduction and strengthening of the immune system. But when the level of fat in the body exceeds a certain level, leptin signaling simply doesn’t work adequately, thus contributing to further weight gain.

References

Ballabh P, Braun A, Nedergaard M. (2004) The blood-brain barrier: an overview: structure, regulation, and clinical implications. Neurobiol Dis 16(1):1-13. doi: 10.1016/j.nbd.2003.12.016

Rhea EM et al. (2017) Blood-Brain Barriers in Obesity. AAPS J. 19, 921-930. doi:10.1208/s12248-017-0079-3.

Obermeier B, Daneman R, Ransohoff RM (2013) Development, maintenance and disruption of the blood-brain barrier. Nature Medicine 19(12): 1584-1596. doi: 10.1038/nm.3407

Burguera B et al. (2000) Obesity is associated with a decreased leptin transport across the Blood-brain barrier in rats. Diabetes 49: 1219-1223. PMID: 10909981

Hsu TM, Kanoski SE (2014) Blood-brain barrier disruption: mechanistic links between Western diet consumption and dementia. Frontiers in Aging Neuroscience 6:88. doi: 10.3389/fnagi.2014.00088

Banks W (2008) The Blood-Brain Barrier as a Cause of Obesity. Current pharmaceutical design 14. 1606-14. PMID: 18673202

Image via strecosa/Pixabay.