The role for adipose tissue in weight regain after weight loss

Abstract

Weight regain after weight loss is a substantial challenge in obesity therapeutics. Dieting leads to significant adaptations in the homeostatic system that controls body weight, which promotes overeating and the relapse to obesity. In this review, we focus specifically on the adaptations in white adipose tissues that contribute to the biological drive to regain weight after weight loss. Weight loss leads to a reduction in size of adipocytes and this decline in size alters their metabolic and inflammatory characteristics in a manner that facilitates the clearance and storage of ingested energy. We present the hypothesis whereby the long-term signals reflecting stored energy and short-term signals reflecting nutrient availability are derived from the cellularity characteristics of adipose tissues. These signals are received and integrated in the hypothalamus and hindbrain and an energy gap between appetite and metabolic requirements emerges and promotes a positive energy imbalance and weight regain. In this paradigm, the cellularity and metabolic characteristics of adipose tissues after energy-restricted weight loss could explain the persistence of a biological drive to regain weight during both weight maintenance and the dynamic period of weight regain.

Keywords: Adipogenesis; dieting; obesity; weight regulation.

Figure 1

Homeostatic adaptations to weight loss that persist in weight maintenance.Neuroendocrine signals from the periphery (green arrows) convey a message of energy depletion (low leptin and insulin) and low nutrient availability (favouring signals of hunger over satiety/satiation) to the brain. Trafficking of absorbed nutrients (glucose, Glu; free fatty acids, FFA; triglycerides, TGs) to and from circulation is shown for both postprandial and post-absorptive metabolic states (blue arrows). Enhanced nutrient clearance reduces postprandial excursions in Glu and TGs and potentiates the postprandial suppression of FFAs, which may also convey a signal of nutrient deprivation to the brain. The signals of energy depletion and nutrient deprivation create an ‘anabolic’ neural profile in the hypothalamus and hindbrain, increasing appetite (solid black arrows) and sending efferent signals to enhance metabolic efficiency in peripheral tissues (purple arrows). The reduced metabolic mass, enhanced metabolic efficiency and lower thermic effect of food contribute to the suppression of energy expenditure (dotted black lines). A large energy gap is created between appetite and expenditure, and food intake must be cognitively (in humans) or forcefully (in animals) restricted to maintain the reduced weight. Adapted from fig. 1 of reference (7).

Figure 2

Adipocyte cellularity changes with weight loss and weight regain.Representative adipocytes are shown in the context of obesity, after weight loss and after weight regain. Weight loss would reduce the average size of resident adipocytes. Weight regain could involve both hypertrophy and hyperplasia. Changes in the neuroendocrine inputs (SNS tone and T3) that may be contributing to the adaptive response to weight loss are shown for each metabolic context. Likewise, changes in the secretion of the long-term adipose signal reflecting stored energy (leptin and insulin) are shown for each metabolic context. Finally, the systemic impact on nutrient availability is presented as the relative flux of glucose, triglycerides (TG) and free fatty acids (FFA). Both long-term (leptin) and short-term (nutrients and their surrogate signals) would be sensed by the hypothalamus and hindbrain to regulate appetite and metabolic requirements.