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Leptin Mediates Obesity Hypertension – End Of Story!



sharma-obesity-obese_miceSome times you think that a scientific question has long been adequately answered when someone comes along and puts any remaining doubts to rest.

This happened last week, when Stephanie Simonds and an international group of researchers, in a paper published in Cell, present a rather elegant and sophisticated range of studies clearly demonstrating that the adipocyte-derived hormone leptin is a key mediator of hypertension in diet-induced (and probably other types of) obesity.

The reason I thought that this question had already long been put to rest was due to a series of rather convincing animal and human studies published in the early 2000s (some of which I was directly involved in) that nicely demonstrated a) that obesity in hypertension is largely mediated by an increase in (renal) sympathetic activity; b) that leptin stimulates sympathetic activity and sodium retention; c) in dogs and humans leptin concentrations are closely correlated with sympathetic nerve activity and blood pressure. We’ve also known that obese mice lacking leptin or its receptor do not develop hypertension despite considerable weight gain.

If anyone should have any remaining questions, these are now answered in the paper by Simonds and colleagues which uses an array of experiments involving animals deficient in leptin or leptin receptors, humans with loss-of-function mutations in leptin and the LepR and show that leptin’s effects on blood pressure are mediated by neuronal circuits in the dorsomedial hypothalamus (DMH), an effect that is prevented or reversed by blocking leptin with a specific antibody, antagonist, or inhibition of the activity of LepR-expressing neurons in the DMH. 

All of this is interesting and highlights the fact that adipose tissue is far more than a simple storage organ for fat but rather a tissue that plays an active role in the regulation of a wide range of bodily functions.

Leptin alone, just one of the many hormones secreted by fat cells (often collectively referred to as adipokines), has been shown to play an important role in appetite and energy regulation, immune function and bone development.

As for bringing us a step closer to obesity treatments, the study suggests that it may not be easily possible to harness leptin as a treatment for weight loss, as one expected side effect would be an increase in blood pressure and heart rate – effects that have limited the clinical tolerability of other “sympathomimetic” drugs.

@DrSharma
Edmonton, AB

2 Comments

  1. 1- How do you identify obesity hypertension (by opposition to hypertension alongside obesity)?

    2- What causes hypertension in normal weight people? Is it really plausible that there are two distinct mechanisms depending on weight?

    I’m asking because I am currently obese and hypertensive, but my hypertension developped during the few years of my life where I maintained a “normal” weight (according to BMI at least). I certainly didn’t have high leptin at the time (I had hypothalamic amenorrhea), but I probably do today. As I gained a lot of weight, my blood pressure didn’t increase but rather decreased a bit. So I guess I am an example of hypertension alongside obesity without the leptin involvement.

    Furthermore, we shouldn’t have to rely on rodent studies: there have been a few leptin studies on humans. I don’t remember reading any concern about a raise in their blood pressure. Maybe the rodent studies don’t apply to humans. Or maybe essential hypertension is too vague a diagnosis, and there are actually many pathologies that raise blood pressure (with or without obesity).

    This is not the end of the story to me!

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    • The easiest way to determine if blood pressure is dependent on weight is to see what happens whey you lose or gain weight. There are, however, many different causes of hypertension (over 20 I can think of off the top of my head), including rather obscure causes like eating too much licorice or radiation to the neck. In some patients, there can well be more than a single cause. Also, don’t forget sleep apnea as a common cause of high blood pressure that may have little to do with leptin. When I said end of story, I was merely referring to the question of whether leptin can cause hypertension – apparently it can.

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