Leptin can regulate the presence of neurons in fat boosting calorie-burning capacity


There’s no doubt that you can lose fat by eating less or moving more – yet after decades of research, the biology underlying this equation remains mysterious.

What really ignites the breakdown of stored fat molecules are nerves embedded in the fat tissue, and a new study now reveals that these fat-burning neurons have previously unrecognized powers.

If they receive the right signal, they have an astonishing capacity to grow.

That signal is the hormone leptin, which is released by the fat cells themselves. In experiments with mice described on July 22 in the journal Nature, the researchers found that the normally bushy network of neural fibers within fat tissue shrinks in the absence of leptin and grows back when the hormone is given as a drug.

These changes were shown to influence the animals’ ability to burn the energy stored in fat.

“While the architecture of the nervous system can change significantly as a young animal develops, we did not expect to find this profound level of neural plasticity in an adult,” says . Jeffrey M. Friedman, a molecular geneticist at The Rockefeller University.

If confirmed in humans, the findings could advance research on obesity and related diseases, and potentially open the door to developing new treatments that target neurons in fat.

Homing in on neurons in fat

The team began by looking at what happens to mice who do not produce leptin on their own, and how they respond when treated with it.

Discovered in Friedman’s lab in 1994, the hormone relays signals between fat deposits and the brain, allowing the nervous system to curb appetite and boost energy expenditure to regulate body weight.

When mice are genetically engineered to stop producing leptin, they grow three times heavier than normal mice. They eat more, move less, and cannot survive in what should be tolerable cold because their body can’t properly utilize fat to generate heat.

Give these mice a dose of leptin, however, and they quickly begin to eat less and move more. But when the researchers treated them longer, for two weeks, more profound changes occurred: the animals started to break down white fat, which stores unused calories, at normal levels, and regained the ability to use another form of fat tissue, brown fat, to generate heat.

It was this slower change that interested the research team, including the first authors of the Nature paper, Putianqi Wang, a graduate student in the lab, and Ken H. Loh, a postdoctoral fellow.

They suspected that changes in neurons outside the brain – those that extend into fat – might explain why this part of the response to leptin took some time.

To the brain and back

Using an imaging technique developed by the lab of Rockefeller’s Paul Cohen to visualize nerves inside fat, the researchers traced leptin’s effects on the fat-embedded neurons up to the brain’s hypothalamus region.

From here, they found, leptin’s growth-promoting message travels via the spinal cord back to the neurons in fat. ù

“This work provides the first example of how leptin can regulate the presence of neurons in fat, both white and brown,” adds Cohen.

Through this pathway, fat appears to be telling the brain how much innervation it needs to function properly. “Fat is indirectly controlling its own innervation and thus function,” Friedman says. “It is an exquisite feedback loop.”

Future research will analyze the role of this pathway in human obesity and possibly provide a novel approach for therapy.

Most obese people produce high levels of leptin, and show a diminished response to hormone injections, suggesting that their brain is resistant to the hormone.

Thus, bypassing leptin resistance could have a therapeutic benefit for these patients.

“In the new study we see that similar to animals lacking leptin, obese, leptin-resistant animals also show reduced fat innervation,” Friedman says.

“So we speculate that directly activating the nerves that innervate fat and restoring a normal ability to use stored fat could provide a possible new avenue for treating obesity.

Leptin is generally considered to affect body energetics in 2 cooperating ways, both counteracting obesity: decreasing appetite as well as increasing the combustion of food (i.e., increasing thermogenesis) (Fig. 1).

Although there is a plethora of review articles on the role of leptin and leptin deficiency on regulation of food intake (and insulin sensitivity, reproduction, immunity etc.) (e.g., (1–7)), there is no comprehensive study on the significance of leptin for thermoregulation, especially with respect to the role of leptin in the control of brown adipose tissue (BAT) activity. This review attempts to fill this gap.

The general picture of leptin action.
Figure 1
The general picture of leptin action.
Leptin, encoded by the ob gene, is expressed in adipocytes (mainly in white adipocytes); its expression is positively correlated with fat mass and regulated in a fasting/feeding-dependent manner. Leptin is secreted and via the circulation reaches its target neurons in hypothalamic nuclei (colored circles, here unspecified) that express the long isoform of the leptin receptor (LepRb, green). Mice carrying the ob mutation lack functional leptin; animals carrying the db mutation (mice) or fa mutation (rats) lack functional LepRb. Leptin action in the hypothalamus activates anorexigenic pathways and is discussed to also trigger mechanisms affecting brown adipose tissue activity and, mainly through this, energy expenditure. The latter two effects are still under debate and are those analyzed in the present review. In the adipocytes: blue circles, nuclei; dark-brown structures mitochondria; yellow circles, lipid droplets; in the neurons: beige circles, leptin.

Knowledge on the thermogenic role of leptin has been obtained from observations on animals that lack leptin function and from direct observations of leptin effects. We therefore first analyze relevant data from the ob/ob mouse (also known as Lepob/Lepob), which lacks the ability to produce leptin, and from the db/db mouse and fa/fa rat, which lacks the leptin receptor.

We then examine the effects of leptin treatment in both leptin-deficient mice and wild-type mice, as well as the effects of leptin in humans. We conclude that leptin is a pyrexic hormone (increases the regulated body temperature) but that it is not thermogenic, at least not in the standard mouse models used, and that the obesity in the ob/ob mice thus evolves without reinforcement from decreased thermogenesis.

The Effects of Leptin
In 1994, the Friedman laboratory determined the nature of the genetic defect in the ob/ob mice and thus identified leptin (16).

Leptin (derived from the Greek word leptos, meaning “thin”) was the name given to the protein normally encoded by the ob gene.

Leptin is a hormone secreted by adipocytes and that acts primarily in the hypothalamus (7). Leptin treatment leads to reduction in food intake and thus in body mass in ob/ob mice (52,211,212), demonstrating that it was indeed the lack of leptin that caused obesity in the ob/ob mice.

It was thus logical to also study the effects of leptin treatment and leptin replacement in ob/ob mice on body temperature regulation, energy expenditure, and BAT physiology.

All studies on the effects of leptin treatment performed on ob/ob have been performed in mice on the C57BL/6 background.

The results of these studies will be discussed in the following sections, but, as summarized previously, it should be remembered that the ob/ob mice do not really demonstrate any hypometabolic or BAT atrophy phenotype.

Leptin is a Pyrexic Agent
The leptin-deficient ob/ob mice display changes in the temperature threshold for their thermoregulatory effectors. They show a lower but defended body temperature at subthermoneutral temperatures.

Therefore, leptin replacement in ob/ob mice is expected to normalize body temperature. Indeed, body temperature in ob/ob mice living at room temperature is increased after acute (within hours) (35), semiacute (within 2 days) (53) or chronic treatment with leptin (35,52,53,213,214) (Fig. 6B,D,F).

In pair-fed animals, body temperature was only increased after long-term treatment (54). In some reports, there is also a slight positive effect of long-term leptin treatment on body temperature at thermoneutrality (35,214).

Thus, leptin clearly has an effect on body temperature in ob/ob mice (Fig. 6B,D,F). The slightly increased body temperature in ob/ob mice at thermoneutrality and the increase in body temperature back to wild-type levels below thermoneutrality point towards a pyrexic response (i.e., an increase in the defended body temperature) (Fig. 6C,E).

The increase in body temperature, however, does not necessarily mean that thermogenesis is increased; also, alterations in heat retention can contribute to the pyrexic response (35,60).

Leptin is a pyrexic and not a thermogenic agent.
Leptin is a pyrexic and not a thermogenic agent.
(A) Leptin treatment has no effect on energy expenditure in ob/ob mice under thermoneutral or subthermoneutral temperatures. (B) Leptin treatment acutely increases body temperature in ob/ob mice at subthermoneutral temperatures. (C, E) This effect is, however, not a thermogenic response, but a pyrexic (febrile) increase in body temperature because it leads to a seemingly higher “defended” body temperature through an increase in the activation threshold of heat-conserving, but not behavioral, effectors. The increase in body temperature following leptin treatment is not due to increased thermogenesis, but is mainly due to decreased heat loss. (D, F) Leptin replacement in ob/ob mice reduces food intake and adiposity. Additionally, it acutely increases body temperature in ob/ob mice, mainly by decreasing heat loss from the tail.

Leptin in Humans
The discovery of leptin and its profound effects on body weight led to a search for humans with disturbances in leptin signalling. Indeed, leptin-deficient patients were found. However, while these patients displayed massive obesity (245), Farooqi et al. (246) found that the body temperature of a leptin-deficient child was normal and unaffected by leptin treatment.

Although this may look different from data obtained in mouse studies, this child was most likely constantly under thermoneutral conditions, where ob/ob mice also display normal body temperature.

There are several reports of energy expenditure in leptin-deficient patients. Energy expenditure in leptin-deficient humans is similar to that in controls (247) or even higher, at least before adjustment for lean body mass differences (246).

These findings thus seem to be in agreement with the data obtained in ob/ob mice at thermoneutrality, showing no difference in energy expenditure, or even higher energy expenditure.

Leptin treatment of leptin-deficient humans does not affect energy expenditure (248) or may slightly reduce energy expenditure, even when normalized to lean mass (246). However, others found that weight loss in leptin-deficient humans induced by diet restriction led to a reduction in energy expenditure. This did not happen when weight loss was achieved by leptin treatment (247).

It thus seems that leptin deficiency and leptin treatment do not affect energy expenditure or body temperature in humans under standard conditions. This is again in agreement with the data observed in mice, especially when experiments are performed at thermoneutrality. Also, in nonobese humans that do not display leptin deficiency, leptin treatment has been reported not to affect energy expenditure (249).

Weight loss and fasting are physiological states demonstrating low leptin levels. As stated earlier, leptin treatment of fasted wild-type mice can prevent the drop in body temperature and energy expenditure usually observed under these conditions.

It may thus be speculated that similar effects should also be observed in humans. Indeed, several studies measured effects of leptin treatment on energy expenditure in humans during or after weight-loss, as summarized in (250) and outlined next.

In contrast to effects of leptin treatment in food-restricted mice, Fogteloo et al. (251) found no significant effect of leptin treatment in a study of obese humans during moderate caloric restriction. Others found that leptin was not able to prevent the drop in energy expenditure seen during caloric restriction in obese men (252) or during caloric restriction in overweight men (253,254).

In patients after weight loss, energy expenditure is significantly reduced (255). Several reports showed that leptin treatment can ameliorate or prevent the reductions in total energy expenditure in human cohorts after weight loss achieved by dietary restriction (256–258), while no effect was found in patients where weight loss had been achieved by Roux-en-Y gastric bypass surgery (259).

Since also body temperature is reduced in humans after weight loss and caloric restriction (260–262), it seems reasonable to speculate that leptin, through its pyrexic effect, prevents a decrease in body temperature, thereby also affecting metabolism.

Taken together, the data on energy expenditure in humans suffering from leptin deficiency and humans receiving leptin treatment are remarkably similar to those obtained in mice. Leptin deficiency in humans does not seem to lead to reductions in energy expenditure or body temperature, just as it does not in ob/ob mice under thermoneutral conditions.

Leptin treatment of these patients and of lean individuals does not affect energy expenditure, while in some states of physiological reduction of leptin levels, such as weight loss, leptin may prevent the drop in body temperature with the result that energy expenditure is increased.

The obese phenotype of the leptin-deficient ob/ob mouse has led to numerous investigations of the underlying cause of this dramatic phenotype. In addition to the irrefutable role of increased food intake in the development of their obesity, defects in energy metabolism, an inability to defend body temperature in cold environments, as well as atrophied BAT, have been held responsible for partially causing the adiposity in ob/ob mice (Fig. 1).

However, published data on the effects of leptin deficiency on energy metabolism and BAT do not support these conclusions (Fig. 9).

An updated picture of leptin action.
An updated picture of leptin action.
Leptin acts in the brain to suppress food intake, and thereby leads to body weight reduction. Through its pyrexic effect, leptin controls body temperature by differentially regulating effector thresholds. However, and in contrast to the commonly accepted view, leptin has no thermogenic effect. It does not activate BAT-dependent thermogenesis, as is evident from the absence of an effect on energy expenditure. Leptin does not lead to thermogenic recruitment of BAT, but there are indications that leptin can affect sympathetic nerve growth and activity, thereby regulating lipolysis. Although leptin thus clearly affects food intake and body temperature thresholds, current experimental evidence neither supports an acute thermogenic effect of leptin, nor an effect on BAT thermogenic capacity. Leptin does, however, seem to affect the sympathetic innervation (and activity) in BAT and WAT, thereby affecting lipolysis and fuel supply, an effect calling for in-depth analysis in future studies.

Thus, in contrast to common understanding, leptin-deficient mice are not hypometabolic, but rather hypermetabolic under most conditions, an observation that can easily be overlooked when misleading normalization of energy expenditure is used.

This is, however, in agreement with reports showing no difference or even higher energy expenditure in leptin-deficient humans. Under certain conditions, such as low leptin levels induced by weight loss or starvation, leptin replacement can, however, indeed increase energy expenditure in mice, rats, and humans.

This is due to its ability to prevent reductions in body temperature and associated hypometabolic responses that usually occur in such situations.

Detailed examination of the literature on the role of leptin in the regulation of body temperature reveals that leptin-deficient ob/ob mice, rather than being unable to defend their body temperature, display a shift of the activation thresholds of thermoregulatory effectors toward lower temperatures, leading to a lower defended body temperature at subthermoneutral temperatures.

This is rapidly corrected following leptin treatment because of the pyrexic effect of leptin, an effect that to some extent is also observed in wild-type mice. This response is, however, not associated with increases in thermogenesis or BAT recruitment, but rather mediated by decreases in heat loss.

Despite showing increased levels of lipid accumulation in BAT, BAT protein content and mitochondrial respiratory capacity are normal in most strains of leptin-deficient mice. UCP1 mRNA and protein levels, as well as the response to sympathomimetic drugs, are largely unaltered in ob/ob mice on the C57BL/6 background.

Leptin-deficient mice on the outbred Aston background, as well as mice or rats lacking leptin receptors, show some signs of BAT atrophy as estimated from a slower response to cold.

Most of these models display differences in GDP-binding and NE turnover; a phenotype presently not fully understood. Nevertheless, the quantitative significance of this apparent BAT atrophy for the development of obesity has yet to be established.

Slow activation of BAT in response to cold exposure can probably not explain the acute cold intolerance of leptin-deficient mice because the acute response to cold mainly relies on shivering.

A reduction in sympathetic activity in WAT may, however, result in impaired fuel supply for muscle shivering, thereby limiting shivering endurance and impairing the cold defense. We therefore think that the concept that leptin is thermogenic is probably misleading and has directed research efforts into less fruitful directions.

More information: A leptin–BDNF pathway regulating sympathetic innervation of adipose tissue, Nature (2020). DOI: 10.1038/s41586-020-2527-y


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