Implications of crosstalk between leptin and insulin signaling during the development of diet-induced obesity

Abstract

Insulin and leptin play complementary roles in regulating the consumption, uptake, oxidation and storage of nutrients. Chronic consumption of diets that contain a high proportion of calories from saturated fat induces a progressive deterioration in function of both hormones. Certain rat lines and strains of mice are particularly sensitive to the obesogenic and diabetogenic effects of high fat diets, and have been used extensively to study the developmental progression of insulin and leptin resistance in relation to the increasing adiposity that is characteristic of their response to these diets. Some aspects of the diminished efficacy of each hormone are secondary to increased adiposity but a consensus is emerging to support the view that direct effects of dietary components or their metabolites, independent of the resulting obesity, play important roles in development of insulin and leptin resistance. In this minireview, we will examine the implications of crosstalk between leptin and insulin signaling during the development of diet-induced obesity, emphasizing potential interactions between pathways that occur among target sites, and exploring how these interactions may influence the progression of obesity and diabetes.

Figure 1. Interactions between insulin and leptin signaling in mice reared on low fat diets (Panel A), mice reared for 4–8 wks after weaning on 45 kcal% high fat diet (Panel B), and mice after chronic consumption (4–5 mo after weaning) of high fat diet (Panel C)

Animals placed on a low fat diet (Panel A) exhibit normal systemic insulin sensitivity. After a meal, insulin shuts down hepatic glucose production, via both direct and indirect pathways, and promotes glucose uptake in muscle and adipose tissue. The subsequent release of leptin from adipose tissue suppresses food intake and stimulates the sympathetic tonus, which ensures lipid mobilization and fatty acid oxidation during fasting. Mice fed a high fat diet for a short period of time (Panel B) display hepatic insulin resistance, despite preserved insulin sensitivity in muscle and adipose tissue. The loss of hepatic insulin sensitivity is most likely caused by the direct actions of high fat availability on gluconeogenesis or the hypothalamus, which would suppress hepatic glucose output under normal conditions via a vagal pathway. This period of selective hepatic insulin resistance is characterized by increased circulating glucose levels, hyperinsulinemia and a significant increase in fat deposition. When these mice are kept on a high fat diet for a longer period of time (Panel C), hepatic insulin resistance becomes more severe. Initially the peripheral tissues still maintain insulin sensitivity, but the exacerbated fat accumulation in adipose tissue and subsequent hyperleptinemia cause hypothalamic leptin resistance via the induction of SOCS3 and PTP1B. Basal hyperinsulinemia and chronic high fat availability have also been shown to promote a condition in which incomplete fatty acid oxidation and accumulation of lipotoxic short chain fatty acids occurs in peripheral tissues, ultimately leading to a complete loss of their insulin sensitivity.

Figure 1. Interactions between insulin and leptin signaling in mice reared on low fat diets (Panel A), mice reared for 4–8 wks after weaning on 45 kcal% high fat diet (Panel B), and mice after chronic consumption (4–5 mo after weaning) of high fat diet (Panel C)

Animals placed on a low fat diet (Panel A) exhibit normal systemic insulin sensitivity. After a meal, insulin shuts down hepatic glucose production, via both direct and indirect pathways, and promotes glucose uptake in muscle and adipose tissue. The subsequent release of leptin from adipose tissue suppresses food intake and stimulates the sympathetic tonus, which ensures lipid mobilization and fatty acid oxidation during fasting. Mice fed a high fat diet for a short period of time (Panel B) display hepatic insulin resistance, despite preserved insulin sensitivity in muscle and adipose tissue. The loss of hepatic insulin sensitivity is most likely caused by the direct actions of high fat availability on gluconeogenesis or the hypothalamus, which would suppress hepatic glucose output under normal conditions via a vagal pathway. This period of selective hepatic insulin resistance is characterized by increased circulating glucose levels, hyperinsulinemia and a significant increase in fat deposition. When these mice are kept on a high fat diet for a longer period of time (Panel C), hepatic insulin resistance becomes more severe. Initially the peripheral tissues still maintain insulin sensitivity, but the exacerbated fat accumulation in adipose tissue and subsequent hyperleptinemia cause hypothalamic leptin resistance via the induction of SOCS3 and PTP1B. Basal hyperinsulinemia and chronic high fat availability have also been shown to promote a condition in which incomplete fatty acid oxidation and accumulation of lipotoxic short chain fatty acids occurs in peripheral tissues, ultimately leading to a complete loss of their insulin sensitivity.

Figure 1. Interactions between insulin and leptin signaling in mice reared on low fat diets (Panel A), mice reared for 4–8 wks after weaning on 45 kcal% high fat diet (Panel B), and mice after chronic consumption (4–5 mo after weaning) of high fat diet (Panel C)

Animals placed on a low fat diet (Panel A) exhibit normal systemic insulin sensitivity. After a meal, insulin shuts down hepatic glucose production, via both direct and indirect pathways, and promotes glucose uptake in muscle and adipose tissue. The subsequent release of leptin from adipose tissue suppresses food intake and stimulates the sympathetic tonus, which ensures lipid mobilization and fatty acid oxidation during fasting. Mice fed a high fat diet for a short period of time (Panel B) display hepatic insulin resistance, despite preserved insulin sensitivity in muscle and adipose tissue. The loss of hepatic insulin sensitivity is most likely caused by the direct actions of high fat availability on gluconeogenesis or the hypothalamus, which would suppress hepatic glucose output under normal conditions via a vagal pathway. This period of selective hepatic insulin resistance is characterized by increased circulating glucose levels, hyperinsulinemia and a significant increase in fat deposition. When these mice are kept on a high fat diet for a longer period of time (Panel C), hepatic insulin resistance becomes more severe. Initially the peripheral tissues still maintain insulin sensitivity, but the exacerbated fat accumulation in adipose tissue and subsequent hyperleptinemia cause hypothalamic leptin resistance via the induction of SOCS3 and PTP1B. Basal hyperinsulinemia and chronic high fat availability have also been shown to promote a condition in which incomplete fatty acid oxidation and accumulation of lipotoxic short chain fatty acids occurs in peripheral tissues, ultimately leading to a complete loss of their insulin sensitivity.