Obesity and leptin resistance: distinguishing cause from effect

Abstract

Because leptin reduces food intake and body weight, the coexistence of elevated leptin levels with obesity is widely interpreted as evidence of 'leptin resistance.' Indeed, obesity promotes a number of cellular processes that attenuate leptin signaling (referred to here as 'cellular leptin resistance') and amplify the extent of weight gain induced by genetic and environmental factors. As commonly used, however, the term 'leptin resistance' embraces a range of phenomena that are distinct in underlying mechanisms and pathophysiological implications. Moreover, the induction of cellular leptin resistance by obesity complicates efforts to distinguish the mechanisms that predispose to weight gain from those that result from it. We suggest a framework for approaching these issues and important avenues for future investigation.

Figure 1

Schematic diagram of LepRb signaling and mechanisms of cellular leptin resistance. Leptin binding promotes the activation of LEPR-B-associated Jak2, which phosphorylates three tyrosine residues on the intracellular tail of LEPR-B. Each of these phosphorylated residues recruits a unique set of downstream signaling molecules. Phosphorylated Tyr985 (pY985) recruits SHP2 (which participates in ERK activation) and SOCS3 (an inhibitor of LEPR-B signaling). pY1077 recruits the transcription factor STAT5, while pY1138 recruits STAT3. A variety of processes contribute to the attenuation of LEPR-B signaling (red lines), including the feedback inhibition that occurs by STAT3-promoted SOCS3 accumulation. PTP1B, ER stress, and inflammatory signals may also participate in the inhibition of LEPR-B signaling in obesity.

Figure 2

Determination of settling point for food intake. (a) Schematic of mechanisms that contribute to food intake, with those factors that exert pressure to decrease feeding listed on top, and those that tend to increase feeding listed on bottom. (c) Initial response to increased palatability/availability of food. This increases feeding by increasing the drive to eat. (c) New equilibrium for food intake in the continued presence of increased food palatability/availability. Increased feeding promotes increased adiposity, which increases leptin action to promote earlier satiation and additional effects to decrease feeding toward the initial baseline. With obesity, cellular mediators of leptin resistance are promoted in the hypothalamus, limiting leptin action and increasing the amount of leptin/adiposity required to suppress feeding.

Figure 2

Determination of settling point for food intake. (a) Schematic of mechanisms that contribute to food intake, with those factors that exert pressure to decrease feeding listed on top, and those that tend to increase feeding listed on bottom. (c) Initial response to increased palatability/availability of food. This increases feeding by increasing the drive to eat. (c) New equilibrium for food intake in the continued presence of increased food palatability/availability. Increased feeding promotes increased adiposity, which increases leptin action to promote earlier satiation and additional effects to decrease feeding toward the initial baseline. With obesity, cellular mediators of leptin resistance are promoted in the hypothalamus, limiting leptin action and increasing the amount of leptin/adiposity required to suppress feeding.

Figure 2

Determination of settling point for food intake. (a) Schematic of mechanisms that contribute to food intake, with those factors that exert pressure to decrease feeding listed on top, and those that tend to increase feeding listed on bottom. (c) Initial response to increased palatability/availability of food. This increases feeding by increasing the drive to eat. (c) New equilibrium for food intake in the continued presence of increased food palatability/availability. Increased feeding promotes increased adiposity, which increases leptin action to promote earlier satiation and additional effects to decrease feeding toward the initial baseline. With obesity, cellular mediators of leptin resistance are promoted in the hypothalamus, limiting leptin action and increasing the amount of leptin/adiposity required to suppress feeding.