Satiety hormone leptin plays a direct role in cardiovascular disease in obesity

October 07, 2015

AUGUSTA, Ga. - While high levels of the satiety hormone leptin don't help obese individuals lose weight, they do appear to directly contribute to their cardiovascular disease, researchers report.

"With obesity, leptin cannot tell our brain to stop eating, but it can still tell our brain to increase the activity of the cardiovascular system," said Dr. Eric Belin de Chantemele, physiologist in the Department of Physiology at the Medical College of Georgia at Georgia Regents University.

In both cell culture and animal models, the researchers have shown that fat-derived leptin directly activates aldosterone synthase expression in the adrenal glands, resulting in production of more of the steroid hormone aldosterone.

High aldosterone levels are known to contribute to widespread inflammation, blood vessel stiffness and scarring, enlargement and stiffness of the heart, impaired insulin sensitivity and more.

Aldosterone, which is produced by the adrenal gland, has a direct effect on blood pressure by regulating salt-water balance in the body. High levels of aldosterone are an obesity hallmark and a leading cause of metabolic and cardiovascular problems. But exactly how it gets high in obesity was a mystery.

Identifying the direct connection of high levels of aldosterone and leptin make either a good treatment target to help avoid cardiovascular disease in obesity, the researchers write in the American Heart Association journal Circulation. Their laboratory studies indicate that targeting either disconnects the link and associated cardiovascular problems.

There are already drugs out there that could work, including the old blood pressure drug, spironolactone, that directly targets aldosterone but is rarely used as a frontline blood pressure therapy, said Belin de Chantemele, the study's corresponding author. Spironolactone, a diuretic, helps the kidney eliminate water and sodium but hold onto valuable potassium, according to MedlinePlus. One way it works is by blocking the receptor to which aldosterone binds. There are also leptin receptor blockers under study for a wide range of problems from obesity to cancer.

It seems a bit of physiological irony that fat makes leptin. In fact, fat from a woman makes even more leptin than the exact same amount of fat from a man, although why remains another mystery. Either way, obese individuals become insensitive to leptin's impact on their metabolic, but not their cardiovascular system. Exactly why the brain becomes insensitive to the metabolic effect is yet another mystery, although there are theories about dysfunctional signaling and resistance by the protective blood-brain barrier to letting leptin in, Belin de Chantemele said.

His interest in leptin as an aldosterone trigger was kindled by a 1999 study by German scientists showing that something in fat cells, or adipocytes, was stimulating aldosterone. The fact that obese individuals have high levels of both aldosterone and leptin has been known. Mice he studied with severe endothelial dysfunction - stiff blood vessels and fibrotic hearts - began to put the two together for him. Because these mice, not surprisingly, had high levels of aldosterone and were also hypersensitive to leptin.

The researchers went back to cell culture and put increasing doses of leptin on adrenal cells. They saw increased levels of aldosterone as a result. When they inhibited the leptin receptor, the increases didn't happen. They did similar studies in fat and lean mice alike, and the association kept showing up: the higher the leptin dose, the higher the aldosterone level. When they used inhibitors of hormones already associated with aldosterone, such as angiotensin II, leptin still increased aldosterone. An exception was that fat mice deficient in leptin receptors did not experience high levels of aldosterone. "It's clearly a direct link between leptin and aldosterone," Belin de Chantemele said.

Now they want to see how well the link holds in humans. He and colleagues Dr. Thad Wilkins, professor in the MCG Department of Family Medicine, and Dr. Miriam Cortez-Cooper, associate professor in the GRU Department of Physical Therapy, are starting to look at leptin-aldosterone interaction and levels in 40 overweight men and women who are not taking any cardiovascular medication. They have early evidence, in humans and animals, that the correlation will be strongest in the females, who make so much more leptin.

"We want to see if we can confirm what we are seeing in mice in the human population," Belin de Chantemele said. "If we see that, that probably tells us a blocker of aldosterone action, such as spironolactone, would be a good treatment particularly for obese females."

He notes that high aldosterone levels in obesity are not associated with the usual suspects: angiotensin II, a hormone known to constrict blood vessels; the steroid hormone cortisol; and the adrenocorticotropic hormone, or ACTH, all are known to control aldosterone secretion. In fact, obesity is often associated with low or usual levels of all these, Belin de Chantemele said.
The research was funded by a Scientist Development Grant from the American Heart Association.

Toni Baker
Communications Director
Medical College of Georgia
Georgia Regents University
706-721-4421 Office
706-825-6473 Cell

Medical College of Georgia at Augusta University

Related Obesity Articles from Brightsurf:

11 years of data add to the evidence for using testosterone therapy to treat obesity, including as an alternative to obesity surgery
New research covering 11 years of data presented at this year's European and International Congress on Obesity (ECOICO 2020) show that, in obese men suffering from hypogonadism (low testosterone), treatment with testosterone injections lowers their weight and improves a wide range of other metabolic parameters.

Overlap between immunology of COVID-19 and obesity could explain the increased risk of death in people living with obesity, and also older patients
Data presented in a special COVID-19 session at the European and International Congress on Obesity (ECOICO 2020) suggests that there are overlaps between the immunological disturbances found in both COVID-19 disease and patients with obesity, which could explain the increased disease severity and mortality risk faced by obese patients, and also elderly patients, who are infected by the SARS-CoV-2 virus that causes COVID-19 disease.

New obesity guideline: Address root causes as foundation of obesity management
besity management should focus on outcomes that patients consider to be important, not weight loss alone, and include a holistic approach that addresses the root causes of obesity, according to a new clinical practice guideline published in CMAJ (Canadian Medical Association Journal)

Changing the debate around obesity
The UK's National Health Service (NHS) needs to do more to address the ingrained stigma and discrimination faced by people with obesity, says a leading health psychologist.

Study links longer exposure to obesity and earlier development of obesity to increased risk of type 2 diabetes
Cumulative exposure to obesity could be at least as important as actually being obese in terms of risk of developing type 2 diabetes (T2D), concludes new research published in Diabetologia (the journal of the European Association for the Study of Diabetes [EASD]).

How much do obesity and addictions overlap?
A large analysis of personality studies has found that people with obesity behave somewhat like people with addictions to alcohol or drugs.

Should obesity be recognized as a disease?
With obesity now affecting almost a third (29%) of the population in England, and expected to rise to 35% by 2030, should we now recognize it as a disease?

Is obesity associated with risk of pediatric MS?
A single-center study of 453 children in Germany with multiple sclerosis (MS) investigated the association of obesity with pediatric MS risk and with the response of first-line therapy in children with MS.

Women with obesity prior to conception are more likely to have children with obesity
A systematic review and meta-analysis identified significantly increased odds of child obesity when mothers have obesity before conception, according to a study published June 11, 2019 in the open-access journal PLOS Medicine by Nicola Heslehurst of Newcastle University in the UK, and colleagues.

Obesity medicine association announces major updates to its adult obesity algorithm
The Obesity Medicine Association (OMA) announced the immediate availability of the 2019 OMA Adult Obesity Algorithm, with new information for clinicians including the relationship between Obesity and Cardiovascular Disease, Diabetes Mellitus, Dyslipidemia, and Cancer; information on investigational Anti-Obesity Pharmacotherapy; treatments for Lipodystrophy; and Pharmacokinetics and Obesity.

Read More: Obesity News and Obesity Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to