What if obesity could be cured without exercising more or eating differently? While these interventions can lead to weight loss, for people struggling with obesity, they are often not enough.

“Obesity is the chronic disturbance of energy homeostasis,” explained Shingo Kajimura, an obesity researcher at Harvard University. “It's really about a failure in energy balance between food intake and energy expenditure, so if you chronically eat more than what you are going to use, you gain weight because extra energy is stored in fat cells.”

Current treatments for obesity include bariatric surgery and therapeutics that suppress appetite or inhibit lipid absorption in the gut. Often, however, obese patients don’t qualify for bariatric surgery, and the approved obesity medications have detrimental side effects, including gastrointestinal problems  and depression.

“All of the anti-obesity medications target food intake,” said Kajimura. “There's no medication that increases energy expenditure so far. That's sort of the Holy Grail.”

In a recent study published in Nature Metabolism, scientists reported a way to target the other side of the weight loss coin: energy expenditure (1). The researchers treated obese mice with extracellular vesicles (EVs) that carried a plasmid encoded to activate specific neurons in the hypothalamus. This neural activation stimulated brown fat thermogenesis, a process that releases energy from adipose tissue in the form of heat. This treatment led to significant weight loss in the mice.

Brown adipose tissue can be thought of as an internal furnace. When it’s cold outside, peripheral nerves in the skin send a signal to the hypothalamus, which then sends signals to nerves in the brown adipose tissue to stimulate thermogenesis. Small mammals like rodents have a much larger ratio of brown fat to body weight than adult humans do because rodents use brown fat thermogenesis to regulate their body temperatures. While adult humans have significantly less brown adipose tissue than rodents, they have enough that its thermogenesis could still significantly influence metabolism (2).

Miguel López, a metabolism researcher at the University of Santiago de Compostela and co-senior author of the new study, and his team had previously shown that inhibiting the expression of AMP-activated protein kinase (AMPK), an important regulator of cell energy balance, increased nervous system signaling to brown adipose tissue, promoting thermogenesis and weight loss in rodents (3). Specifically, inhibiting AMPK in neurons that express the protein SF1 in the ventromedial region of the hypothalamus (VMH) protected against diet-induced obesity (4).

But how could his team alter AMPK signaling specifically in the SF1 neurons in the VMH and nowhere else in the body? For that, López teamed up with his long-time collaborator Ramaroson “Naina” Andriantsitohaina, a researcher at the French Institute of Health and Medical Research (INSERM) and co-senior author of the study who investigates the role of EVs  in metabolic diseases.

“Naina's approach is fantastic because these vesicles basically can cross any biological barrier because they are very small, but they can be loaded with cargos that can be specifically directed to a specific cell population,” López said.

Together, López and Andriantsitohaina’s teams spent three years designing their EVs. To target the vesicles to neurons in the VMH, they derived them from immature dendritic cells and engineered them to express a fusion protein that facilitates blood-brain barrier crossing. Using an SF1-specific promoter sequence, they demonstrated that when they administered the EVs via the bloodstream, the EVs delivered a plasmid encoding a dominant negative form of AMPK only to SF1-expressing neurons in the VMH. The researchers did not see expression of the plasmid in other tissues that express SF1, such as the adrenal or pituitary glands, and they did not see plasmid expression in non-SF1-expressing neurons.

“Twenty-six years ago, [when] I was busy studying and I was starting work in the hypothalamus, if someone told me this, I would think at that time that this is science fiction,” said López.

While eating and exercising the same amount, obese mice treated with the EVs showed evidence of enhanced brown adipose tissue thermogenesis and experienced significant weight loss after six days. The mice kept the weight off for two weeks after the researchers halted the EV treatment, and when treatment resumed, the mice lost the weight again.

Most importantly, López added, the increased brown adipose tissue thermogenesis triggered by the EV-treatment didn’t lead to any adverse cardiovascular side effects. Prior efforts to stimulate thermogenesis for weight loss were plagued by patients experiencing increased blood pressures and heart rates.

Christopher Madden, a neuroscientist and metabolism researcher at Oregon Health and Science University who was not involved in the study but who co-authored an accompanying editorial on the paper, was surprised that the researchers did not see any evidence of increased heart rates due to the increased thermogenesis (5).

“When brown adipose tissue is activated, it creates heat,” said Madden. “That heat is then distributed through the rest of the body through the blood supply… so, in order to maintain blood pressure, cardiac output has to go up.” It’s possible that with their method, the researchers are activating a separate pathway that induces thermogenesis without affecting blood pressure, Madden added, but further experiments to clarify the mechanism underlying this finding are needed.

Madden is also curious about how the researchers’ EV treatment might affect the other processes that SF1 neurons regulate, such as aggression and fear behaviors, reproduction, and glucose homeostasis.

“The significance of this paper is really the new strategy to selectively target these SF positive neurons in the hypothalamus using the new extracellular vesicles, and then activate sympathetic nerves,” said Kajimura, who was also not involved in the study. From a “drug delivery perspective, I think that's a very fascinating technology,” he added.

Madden agreed with Kajimura on the drug-delivery potential of the researchers’ EV treatment. “It could have a large impact on the greater neuroscience field,” Madden said. “It could serve to draw attention to this as a delivery vehicle to get therapeutics that require access to the central nervous system.”

López and Andriantsitohaina are already focusing their EV technology on other targets and continue to study their EVs in the context of AMPK and obesity. They plan to formulate their EVs for intranasal administration, which would make a potential obesity treatment easier for patients.

“It will be absolutely great if we can contribute to a cure and treat obesity or any other disease that can be applied to the use of this strategy,” said López. “The method opens also the door to treat any other brain diseases that are complicated to treat.”

References

1. Milbank, E. et al. Small extracellular vesicle-mediated targeting of hypothalamic AMPKα1 corrects obesity through BAT activation. Nat Metab  3, 1415–1431 (2021).
2. Leitner, B.P. et al. Mapping of human brown adipose tissue in lean and obese young men. Proc Nat Acad Sci USA  114, 8649-8654 (2017).
3. López, M. et al. Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nat Med  16, 1001-1008 (2010).
4. Seoane-Collazo, P. et al. SF1-Specific AMPKα1 Deletion Protects Against Diet-Induced Obesity. Diabetes  67, 2213-2226 (2018).
5. Mota, C.M.D., Madden, C.J. A blood-to-brain delivery system to treat obesity. Nat Metab  3, 1288-1289 (2021).