Starvation in the Midst of Plenty: Reflections on the History and Biology of Insulin and Leptin

Abstract

Insulin and leptin are critical metabolic hormones that play essential but distinct roles in regulating the physiologic switch between the fed and starved states. The discoveries of insulin and leptin, in 1922 and 1994, respectively, arose out of radically different scientific environments. Despite the dearth of scientific tools available in 1922, insulin's discovery rapidly launched a life-saving therapy for what we now know to be type I diabetes, and continually enhanced insulin therapeutics are now effectively applied to both major forms of this increasingly prevalent disease. In contrast, although the discovery of leptin provided deep insights into the regulation of central nervous system energy balance circuits, as well as an effective therapy for an extremely rare form of obesity, its therapeutic impact beyond that has been surprisingly limited. Despite an enormous accumulated body of information, many important questions remain unanswered about the mechanisms of action and role in disease of both hormones. Additionally, although many decades apart, both discoveries reveal the complexities inherent to scientific collaboration and the assignment of credit, even when the efforts are spectacularly successful.

Figure 1.

(a) Before and after pictures of a child treated with insulin in 1922. From Bliss (1). (b) Before and after pictures of recombinant leptin treatment in a patient with congenital leptin deficiency. Before, 3 years old weighing 42 kg. After, 7 years old weighing 32 kg. [Reproduced with permission from Farooqi IS, O'Rahilly S. Twenty years of leptin: human disorders of leptin action. J Endocrinol 2014; 223(1):T63–T70. (2)] [© 2019 Illustration Presentation ENDOCRINE SOCIETY]

Figure 2.

Relationships between serum leptin levels and leptin action. The major effects of changing leptin levels on leptin physiologic actions occur between (A) the low levels seen with food restriction or starvation and (B) the rising levels seen with refeeding. Low levels cause increased hunger, decreased energy expenditure, and suppression of the reproductive and thyroid axes and sympathetic nervous system activity. As levels rise with refeeding, hunger diminishes, sympathetic nervous system activity rises, and reproductive and thyroid axes return to normal. (C) With overfeeding, there are two possible patterns for leptin responsiveness. (D) In one, rising leptin serves as a lipostatic signal, acting on hypothalamic centers to further suppress hunger and/or increase sympathetic activity, reducing weight, limiting obesity, and lowering leptin levels. (E) In the other pattern, which is more common, leptin levels rise further, reflecting fat mass as obesity progresses, but these higher leptin levels exert little or no additional effect to suppress hunger or enhance sympathetic activity to resist obesity. [©2019 Illustration Presentation ENDOCRINE SOCIETY]