Leptin resistance and hippocampal behavioral deficits

Abstract

The adipocyte-derived hormone leptin is an important regulator of body weight and metabolism through activation of brain leptin receptors expressed in regions such as the hypothalamus. Beyond these well described and characterized activities of leptin in the hypothalamus, it is becoming increasingly clear that the central activities of leptin extend to the hippocampus. Indeed, leptin receptors are expressed in the hippocampus where these receptors are proposed to mediate various aspects of hippocampal synaptic plasticity that ultimately impact cognitive function. This concept is supported by studies demonstrating that leptin promotes hippocampal-dependent learning and memory, as well as studies indicating that leptin resistance is associated with deficits in hippocampal-dependent behaviors and in the induction of depressive-like behaviors. The effects of leptin on cognitive/behavioral plasticity in the hippocampus may be regulated by direct activation of leptin receptors expressed in the hippocampus; additionally, leptin-mediated activation of synaptic networks that project to the hippocampus may also impact hippocampal-mediated behaviors. In view of these previous observations, the goal of this review will be to discuss the mechanisms through which leptin facilitates cognition and behavior, as well as to dissect the loci at which leptin resistance leads to impairments in hippocampal synaptic plasticity, including the development of cognitive deficits and increased risk of depressive illness in metabolic disorders such as obesity and type 2 diabetes mellitus (T2DM).

Fig. 1.

Behavioral despair is differentially affected in models of leptin resistance. Panel A: In the forced swim test, administration of a pegylated leptin receptor antagonist (Peg-LRA) significantly reduces swimming behaviors while climbing behaviors are unaffected compared to vehicle-treated control rats. Panel B: Virus-mediated downregulation of hypothalamic insulin receptors (Hypo-IRAS) elicits an obesity/MetS phenotype that is associated with depressive-like behaviors, including behavioral despair in the forced swim test [53]. However, both climbing and swimming behaviors are non-significantly reduced in Hypo-IRAS compared to Hypo-Control (Hypo-Con) rats. These differential effects upon ‘active’ behaviors in the FST provide insight into the neurotransmitter systems and circuits that may regulate these behaviors in leptin resistant rodents. See text for details. [* = p < 0.05].

Fig. 2.

Lentivirus-mediated downregulation of hypothalamic leptin receptors significantly increases body weight. Rats received third ventricular injections of either a control lentivirus (LV-Con) or a lentivirus containing an antisense sequence selective for the leptin receptor (LV-LepRAS). Beginning approximately 14 days following virus administration, LV-LepRAS rats exhibit significant increases in body weight compared to LV-Con rats. [* = p < 0.05].

Fig. 3.

Peripheral leptin administration increases the phosphorylation of STAT3 (pSTAT3) in the hypothalamus of LV-Control rats but not in the hypothalamus of LV-LepRAS rats. Rats received an intraperitoneal injection of leptin (5 mg/kg) and brains were processed for pSTAT3 immunohistochemistry as described in our previous studies [27,85]. Left panel depicts representative bright-field micrograph of leptin-induced pSTAT3 immunoreactivity in the ventromedial nucleus of the hypothalamus (VMH) of rats that received third ventricular injections of the LV-Con construct. Right panel depicts representative bright-field micrograph in which leptin-stimulated pSTAT3 immunoreactivity is significantly reduced in the VMH of LV-LepRAS rats. Such results indicate that LV-LepRAS-treated rats develop leptin resistance.

Fig. 4.

Direct and indirect mechanistic circuits through which leptin receptor activity modulates hippocampal-related behaviors. Under physiological conditions, leptin released from adipocytes crosses the blood-brain barrier via a facilitated transport system and activates leptin receptors expressed in the CNS (as depicted in the green arrows and yellow receptor symbols). Activation of hippocampal leptin receptors is proposed to contribute to enhancement of hippocampal-dependent behaviors such as spatial learning and memory. In combination with the activation of hippocampal leptin receptors, activation of leptin receptors in the VTA and the raphe nucleus may directly modulate motivated behaviors and elicit anti-depressant like effects via activation of neuronal circuits that project to the hippocampus (as depicted in the green shaded portion of the figure). While obesity is associated with increases in adiposity and plasma levels of leptin, a characteristic feature of obesity is CNS leptin resistance, which results from a combination of decreased blood-brain barrier transport of leptin and a decrease in leptin receptor signaling (as depicted in the dashed red lines). Under such conditions, the combination of hippocampal leptin resistance and reduced circuit activation from the raphe nucleus and the ventral tegmental area (VTA) would result in impairments in hippocampal-dependent learning and memory and the development of depressive-like behaviors (as depicted in the red-shaded portion of the figure). These observations from pre-clinical studies predict that CNS leptin resistance is a mechanistic link in the cognitive deficits and increased risk for neuropsychiatric disorders in obese individuals. See text for details.