Leptin Mediates a Glucose-Fatty Acid Cycle to Maintain Glucose Homeostasis in Starvation

Abstract

The transition from the fed to the fasted state necessitates a shift from carbohydrate to fat metabolism that is thought to be mostly orchestrated by reductions in plasma insulin concentrations. Here, we show in awake rats that insulinopenia per se does not cause this transition but that both hypoleptinemia and insulinopenia are necessary. Furthermore, we show that hypoleptinemia mediates a glucose-fatty acid cycle through activation of the hypothalamic-pituitary-adrenal axis, resulting in increased white adipose tissue (WAT) lipolysis rates and increased hepatic acetyl-coenzyme A (CoA) content, which are essential to maintain gluconeogenesis during starvation. We also show that in prolonged starvation, substrate limitation due to reduced rates of glucose-alanine cycling lowers rates of hepatic mitochondrial anaplerosis, oxidation, and gluconeogenesis. Taken together, these data identify a leptin-mediated glucose-fatty acid cycle that integrates responses of the muscle, WAT, and liver to promote a shift from carbohydrate to fat oxidation and maintain glucose homeostasis during starvation.

The Role of Leptin in Maintaining Plasma Glucose During Starvation

“…In this model, increased hypothalamic-pituitary-adrenal axis activity, which occurs secondary to an acquired leptin deficiency, is also necessary (40–44). In our hands (45) and others’ (8, 46–68), plasma leptin concentrations and WAT leptin expression have been shown to drop quickly with starvation. To understand the role of this reduction in plasma leptin, Ahima et al performed a classic study in which they performed an intraperitoneal injection of leptin resulting in plasma leptin concentrations initially 100 times normal, and examined various physiologic parameters twelve hours later.…”

“…We hypothesized that the failure of some previous studies to elucidate an acute effect of leptin to rapidly lower plasma glucose concentrations in starvation (60) and in T1D (69–71) may be related to the pharmacokinetics of the leptin administration: typically studies examining the impact of leptin have increased plasma leptin concentrations 10–100 times normal. To test the physiologic impact of supraphysiologic leptin concentrations, we infused stepwise increasing doses of leptin in separate groups of 48 hr fasted and T1D rats and found that while supraphysiologic leptin had no impact on HPA axis activity, which was suppressed by all doses of leptin, high-dose leptin infusion promoted sympathetic activation, increasing WAT lipolysis, hepatic acetyl-CoA content, and gluconeogenesis (45). These data corroborate previous studies in which high concentrations of leptin were shown to cause sympathetic activation by promoting catecholamine synthesis (72) and responsiveness (73), which is reflected in increases in energy expenditure (60, 74–78).…”

“…To a first approximation, leptin concentrations are typically proportional to fat mass (80–84); however the rapid reductions in leptin observed with starvation, which occur out of proportion to body weight changes (45, 52, 53, 55, 58, 60, 67, 85–88), suggest that an additional regulator beyond simply body fat mass may regulate leptin secretion and in particular its alterations with fasting. Several studies have shown that the combination of hyperglycemia and hyperinsulinemia – as occurs in the postprandial period – increases leptin secretion (54, 89–91), though other reports have failed to demonstrate any effect of feeding or short-term hyperglycemia-hyperinsulinemia on leptin concentrations (92–96).…”

“…When we infused a physiologic replacement dose of leptin in 48 hr fasted animals, this intervention caused a rapid reduction in HPA axis activity, suppressing WAT lipolysis and gluconeogenesis, and necessitating infusion of glucose to avoid symptomatic hypoglycemia. We then demonstrated that increases in HPA axis activity, lipolysis, and hepatic acetyl-CoA content – all of which are negatively regulated by leptin – are not only associated but are required for glucose maintenance in starvation: treatment with inhibitors of fat oxidation (etomoxir) and lipolysis (atglistatin) or with an inhibitor of glucocorticoid receptor activity (mifepristone) all resulted in suppression of hepatic glucose production and reductions in plasma glucose and insulin concentrations in starved rats (45). Given the key role of hypoleptinemia and resulting increases in HPA axis activity, lipolysis, hepatic acetyl-CoA, and gluconeogenesis in maintaining plasma glucose concentrations in the starved state, we next sought to determine the signal to the adipocyte to reduce leptin concentrations.…”

“…Treatment with an inhibitor of glycogen phosphorylase – and thus of glycogenolysis – demonstrated that depletion of hepatic glycogen and resulting reductions in plasma glucose and insulin concentrations could explain reductions in plasma leptin concentrations in fasting rats, whereas infusion of glucose in 48 hr fasted rats to cause modest increases in plasma glucose (5 to 6 mM) and insulin (60 to 100 pM) similar to what was measured in the 16 hr fasted state increased leptin and suppressed corticosterone to concentrations measured in 16 hr fasted rats. Finally, in order to place these findings in the broader physiological context, we performed, to our knowledge, the first assessment of how tissue-specific glucose versus fat/ketone oxidation changes between 0 and 48 hrs of fasting, and demonstrate that all tissues examined (brain, heart, liver, kidney, brown adipose tissue, WAT, and skeletal muscle) shift to varying extents from glucose to fat metabolism as the duration of fasting increases (45). These data demonstrate that starvation induces a shift from glucose to fat metabolism which permits survival by allowing the liver to produce adequate glucose through gluconeogenesis to maintain plasma glucose concentrations within the normal range, thereby preserving glucose supply to the heart, brain, and other tissues critical for survival.…”