Unfortunately, many, if not all, obese people are brain damaged.
The damage, detectable by brain MRI, is subtle but potentially significant, like that done by punches to boxers’ heads.
University of Washington researchers revealed in a new paper, co-authored by Stephan Guyenet, that obesity in mice, rats, and humans is associated with, and may in at least some cases be caused by, inflammation and gliosis (scarring) in the brain region that controls eating and body weight, the hypothalamus.
Here’s the paper’s abstract:
Rodent models of obesity induced by consuming high-fat diet (HFD) are characterized by inflammation both in peripheral tissues and in hypothalamic areas critical for energy homeostasis. Here we report that unlike inflammation in peripheral tissues, which develops as a consequence of obesity, hypothalamic inflammatory signaling was evident in both rats and mice within 1 to 3 days of HFD onset, prior to substantial weight gain. Furthermore, both reactive gliosis and markers suggestive of neuron injury were evident in the hypothalamic arcuate nucleus of rats and mice within the first week of HFD feeding. Although these responses temporarily subsided, suggesting that neuroprotective mechanisms may initially limit the damage, with continued HFD feeding, inflammation and gliosis returned permanently to the mediobasal hypothalamus. Consistent with these data in rodents, we found evidence of increased gliosis in the mediobasal hypothalamus of obese humans, as assessed by MRI. These findings collectively suggest that, in both humans and rodent models, obesity is associated with neuronal injury in a brain area crucial for body weight control.
And from the paper’s interesting discussion:
[W]e report that hypothalamic inflammation induced by HFD feeding is a manifestation of neuron injury that in turn triggers a reactive gliosis involving both microglial and astroglial cell populations. Moreover, these responses appear to occur selectively in the ARC and rapidly follow the initiation of a HFD. The transient nature of this hypothalamic response suggests that neuroprotective responses are mounted that limit or reverse the injury during its initial phases, but, with sustained exposure to the HFD, ARC-ME gliosis and injury responses are reestablished. Combined with MRI-based evidence for gliosis in the MBH of obese humans, our findings suggest that, in both humans and rodent DIO models, obesity is associated with neuron injury in a brain area crucial for body weight control. …
[I]n rats and mice that are susceptible to [diet-induced obesity], consumption of a HFD rapidly induces neuron injury in a brain area critical for energy homeostasis. Although local responses appear to limit this injury, recovery is transient, eventually giving way to chronic inflammation, neuron loss, and reactive gliosis. Extending these findings is MRI evidence for gliosis in the hypothalamus of obese humans. Collectively, this work identifies a potential link between obesity and hypothalamic injury in humans as well as animal models.
In this study, the high-fat diet (Research Diets D12492) fed to the rodents that developed hypothalamic injury contained, by calories, 60% fat (10:1 ratio of lard to soybean oil), 20% carbohydrate, and 20% protein.
So at least in rodents, a sustained, freely eaten high-fat diet – which is also hypercaloric, producing weight gain – leads to injury and death of brain neurons. This in turn produces scarring there, followed by obesity.
MRI images show that the same sort of hypothalamic scarring induced by a sustained high-fat diet in rodents also exists in obese people! The heavier the person, the more brain scarring there is.
This makes sense as a causal mechanism. Some people’s brains may be injured by chronically eating a diet that is high in calories and/or fat. (It’s unclear from this study whether carbohydrates or protein play any role.) As neurons in the hypothalamus — a brain region involved in controlling appetite, satiety, and energy expenditure — become inflamed and then die, these people gain excess weight and find it hard to lose.
Perhaps this explains obese people’s leptin resistance, which makes their brains ignore leptin’s signal to stop eating once they’ve consumed enough food. Indeed, brain inflammation has been shown to create the leptin resistance seen in fat mice.
In rodent models of diet-induced obesity (DIO), increased inflammatory signaling in the mediobasal hypothalamus (MBH) similarly contributes to leptin resistance and weight gain.
Postscript: Dr. Guyenet discusses here another role of inflammation in obesity: producing insulin resistance. He notes, “Energy excess causes inflammation, and inflammation causes insulin resistance.”