Leptin and the maintenance of elevated body weight

Key Points

  • The body possesses an energy homeostasis system by which it adjusts food intake to match calories burned to keep body weight stable

  • The hormone leptin, which is made by adipose tissue in approximate proportion to fat stores, plays an important role in the control of energy homeostasis. When fat stores are expended, leptin falls, causing an increase in appetite and diminishing energy expenditure to return fat stores to their previous levels

  • Because obesity results from the accretion of adipose tissue fat stores, leptin levels are high in obesity. The failure of this high leptin (and therapy with exogenous leptin) in the obese state to decrease feeding and return adipose mass to normal has suggested the existence of leptin resistance, in which obesity impairs leptin action

  • Obesity provokes a number of changes to hypothalamic anatomy and physiology, many of which have been invoked as potential mediators of leptin resistance. These include the leptin-induced expression of leptin signalling inhibitors, hypothalamic inflammatory signalling and gliosis and endoplasmic reticulum stress

  • A variety of data suggest that early steps in leptin signalling are appropriately enhanced in response to the high leptin levels in obesity and that elevated leptin itself may attenuate downstream leptin action. Hence, the failure of leptin to decrease food intake and body weight in obesity may result from high leptin levels producing changes that act downstream of the initial steps in leptin signalling to create a functional ceiling for leptin action

  • The available data suggest that leptin functions primarily in defence against decreased body weight rather than in limiting increases in body weight

Abstract

Obesity represents the single most important risk factor for early disability and death in developed societies, and the incidence of obesity remains at staggering levels. CNS systems that modulate energy intake and expenditure in response to changes in body energy stores serve to maintain constant body adiposity; the adipocyte-derived hormone leptin and its receptor (LEPR) represent crucial regulators of these systems. As in the case of insulin resistance, a variety of mechanisms (including feedback inhibition, inflammation, gliosis and endoplasmic reticulum stress) have been proposed to interfere with leptin action and impede the systems that control body energy homeostasis to promote or maintain obesity, although the relative importance and contribution of each of these remain unclear. However, LEPR signalling may be increased (rather than impaired) in common obesity, suggesting that any obesity-associated defects in leptin action must result from lesions somewhere other than the initial LEPR signal. It is also possible that increased LEPR signalling could mediate some of the obesity-associated changes in hypothalamic function.

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Figure 1: Leptin action.
Figure 2: Leptin signalling and mechanisms that mediate its inhibition.
Figure 3: CNS leptin action.
Figure 4: Hypothalamic leptin action and changes during diet-induced obesity.

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Acknowledgements

The authors were supported by the Michigan Diabetes Research Center (P30 DK020572), the American Diabetes Association, the Marilyn H. Vincent Foundation, the US National Institutes of Health (DK56731 and DK78056) and the Cell and Molecular Biology (CMB) Training Grant (T32GM007315). The authors thank D. Olson, D. Sandoval, R. Seeley and members of the Myers laboratory for helpful discussions.

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M.G.M. was involved in researching data for the article, made a substantial contribution to discussion of content and wrote, reviewed and edited the manuscript before submission. W.W.P. was involved in researching data for the article, made a substantial contribution to the discussion of content and wrote, reviewed and edited the manuscript before submission.

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Correspondence to Martin G. Myers Jr.

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Glossary

Energy expenditure

The burning of calories by an organism on normal metabolism (basal metabolic rate) and activity.

Hyperphagia

Literally meaning 'eating too much', it is the consumption of more calories than needed to maintain energy homeostasis and results in the deposition of excess calories in adipose tissue.

Energy homeostasis

The process by which the number of calories eaten are matched to the number of calories burned to maintain a constant body weight; also known as energy balance.

White adipose tissue

The tissue commonly thought of as fat; major depots are found under the skin and inside the abdominal cavity.

Orexigenic

A type of stimuli that increases feeding.

Systemic inflammation

An immune response to infection or other insults that increases the activity of immune cells in the body.

Gut microbiome

The bacteria and other microorganisms that colonize the lumen of the gut.

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Pan, W., Myers, M. Leptin and the maintenance of elevated body weight. Nat Rev Neurosci 19, 95–105 (2018). https://doi.org/10.1038/nrn.2017.168

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