The Use of Animal Models to Dissect the Biology of Leptin

Abstract

Our understanding of the effects of leptin have stemmed mainly from animal studies, which continue to leave important clues of its roles in physiology, metabolism, neuroscience, and cell signaling. Since its discovery, leptin has been linked to various pathways, either directly at its primary site of action in the hypothalamus, or indirectly via downstream effector pathways such as in adipocytes and muscle. Leptin's importance is exemplified by the lack of redundant backup mechanisms, since leptin-deficient mice are obese, diabetic, and sterile. Investigations uncovering the pleiotropic actions of leptin were unfolded mainly from rodent models. Thus, this chapter focuses on these studies and, more specifically, on those findings recently brought forward by transgenic mice overexpressing leptin. The vast amount of biology that has been ascribed to leptin encompasses effects on food intake, insulin sensitivity, adiposity, thermogenesis, reproduction, immunity, and bone regulation. Mechanisms underlying leptin's action revolve essentially around neural pathways but also encompass to a lesser extent peripheral mechanisms. The roles of leptin along these axes are reviewed, with particular emphasis on pathways and phenotypes generated by transgenic hyperleptinemia. An evolutionary significance of hyperleptinemia in association with development of leptin resistance is suggested as a protective armament against some of the detrimental effects caused by hyperleptinemia in transgenic mice overexpressing leptin.

Liver Adenosine Monophosphate-Activated Kinase-α2 Catalytic Subunit Is a Key Target for the Control of Hepatic Glucose Production by Adiponectin and Leptin But Not Insulin

“…This may be due to the modest increase of leptin levels in liver␣2KO mice, compared with that in db/db mice. In genetically engineered or diet-induced rodent models with high plasma levels of leptin, whole-body insulin sensitivity was reduced in a context of leptin resistance (37). Here this is not the case because liver␣2KO mice did not display insulin resistance.…”

The impact of antipsychotic drugs on food intake and body weight and on leptin levels in blood and hypothalamic ob-r leptin receptor expression in wistar rats

“…Its expression and secretion shows a strong positive correlation with body fat mass and adipocyte number and size 8. Leptin, together with other hormones, including glucocorticoids, amylin, and insulin, plays an important role in regulating food intake, energy expenditure, body weight homeostasis,9 reproduction function, and neuroendocrine responses 10. The lack of leptin results in hormonal and metabolic alterations and a dramatic increase in body weight 11.…”

The Intrauterine and Nursing Period Is a Window of Susceptibility for Development of Obesity and Intestinal Tumorigenesis by a High Fat Diet inMin/+Mice as Adults

“…Therefore, in this experiment higher leptin levels were associated with increased body weight (in wild-type mice), whereas lower levels of leptin were associated with lower body weight (in Min/+ mice). The wild-type mice results are more similar to the situation in humans where obesity is associated with elevated levels of leptin, representing a form of leptin resistance [ 55 , 56 ], as opposed to the ob/ob mouse model where the lack of leptin is associated with extreme obesity (see [ 30 , 31 ], Ngo et al, 2014; unpublished results).…”

“…Blood glucose levels were measured and a glucose tolerance test (GTT) was performed to study the hypothesis of disrupted blood glucose regulation as a link between obesity and intestinal tumorigenesis [ 28 , 29 ]. The hormone leptin, which regulates food intake and energy expenditure, as well as having effects on immunity, including inflammation, and reproduction [ 30 , 31 ], was measured in serum from the mice.…”