Set or Settling Point

Setpoint is a term derived from engineering, used to describe a switching point between systems designed to increase or decrease the level of a controlled variable. One example is the setpoint for water level in a reservoir. If the water level rises above the setpoint, an increasing amount of water will be discharged into the outflow. The inflow of water from points upstream might also be reduced. If the water level falls below the optimum level, then the outflow will be reduced in the inflow increased. A setpoint mechanism does not imply full control over a variable, but only a regulated ongoing influence.

Body weight setpoint is thought to operate in a similar manner, with body fat stores as the controlled variable. In the past, the theory of a body weight setpoint was controversial. Some authors misinterpreted the term “setpoint” to mean that body weight was unchangeable, which is clearly not the case. The primary critique of setpoint theory was it required a signal to pass from the adipose tissue to the hypothalamus, and no such signal was known.

This criticism vanished abruptly with the discovery of the hormone leptin. Leptin levels are directly proportion to fat mass, and sufficient levels of leptin trigger decreased input and increased output of stored energy. Falls in leptin levels trigger the opposite effects. Leptin acts as a brake on changes in body fat stores in both the upward and downward direction, precisely the behavior expected of a setpoint process.

Increases in body fat stores trigger several changes that oppose the further accumulation of lipids. (1) Fat storage is an energy requiring process, so some excess calories are consumed transporting and esterifying fatty acids into adipocyte triglyceride droplets. (2) The synthesis of lipids from excess carbohydrates and proteins requires considerable energy, as does the synthesis of the glycerol backbone. (3) Increases in body weight raise the energetic cost of physical activity. (4) Adipose tissue requires a small amount of energy for maintenance, although far less than muscle or other active tissues. (5) Mainly through the influence of leptin, increases in active thyroid hormone and catecholamines raise metabolic rate and increase expression of uncoupling proteins, which increase the generation of heat in competition with energy storage. (6) Most importantly, appetite is suppressed through leptin and other circulating mediators.

Decreases in fat stores trigger the opposite changes. Basal metabolic rate can decline significantly during severe caloric restriction, particularly if there has been loss of lean metabolically active tissue in addition to body fat loss. In countless studies in humans and animals, weight loss has been shown to decelerate over time, with rapid initial losses of body weight slowing to a lower long term rate. Part of the rapid phase is due to fluid loss, especially the loss of water associated with glycogen, but a major portion of the decline in weight loss over time reflects body weight setpoint mechanisms.