Presynaptic Regulation of Leptin in a Defined Lateral Hypothalamus–Ventral Tegmental Area Neurocircuitry Depends on Energy State

Abstract

Synaptic transmission controls brain activity and behaviors, including food intake. Leptin, an adipocyte-derived hormone, acts on neurons located in the lateral hypothalamic area (LHA) to maintain energy homeostasis and regulate food intake behavior. The specific synaptic mechanisms, cell types, and neural projections mediating this effect remain unclear. In male mice, using pathway-specific retrograde tracing, whole-cell patch-clamp recordings and cell type identification, we found that leptin reduces excitatory synaptic strength onto both melanin-concentrating hormone- and orexin-expressing neurons projecting from the LHA to the ventral tegmental area (VTA), which may affect dopamine signaling and motivation for feeding. A presynaptic mechanism mediated by distinct intracellular signaling mechanisms may account for this regulation by leptin. The regulatory effects of leptin depend on intact leptin receptor signaling. Interestingly, the synaptic regulatory function of leptin in the LHA-to-VTA neuronal pathway is highly sensitive to energy states: both energy deficiency (acute fasting) and excessive energy storage (high-fat diet-induced obesity) blunt the effect of leptin. These data revealed that leptin may regulate synaptic transmission in the LHA-to-VTA neurocircuitry in an inverted "U-shape" fashion dependent on plasma glucose levels and related to metabolic states. The lateral hypothalamic area (LHA) to ventral tegmental area (VTA) projection is an important neural pathway involved in balancing whole-body energy states and reward. We found that the excitatory synaptic inputs to both orexin- and melanin-concentrating hormone expressing LHA neurons projecting to the VTA were suppressed by leptin, a peptide hormone derived from adipocytes that signals peripheral energy status to the brain. Interestingly, energy states seem to affect how leptin regulates synaptic transmission since both the depletion of energy induced by acute food deprivation and excessive storage of energy by high-fat diet feeding dampen the suppressive effect of leptin on synaptic transmission. Together, these data show that leptin regulates synaptic transmission and might be important for maintaining energy homeostasis.

Blunted leptin sensitivity during hedonic overeating can be reinstated by activating galanin 2 receptors (Gal2R) in the lateral hypothalamus

“…4 Given that the LHA is innervated by forebrain structures such as the shell of the nucleus accumbens (NAc) and ventral pallidum (VP) 43,56 which are activated by PF (Figure 2A), it is plausible that the aforementioned areas increase LHA neuron excitability and dampen competing inhibitory Gal-ergic inputs (from a presently unknown brain area) to OX neurons. 4 Given that the LHA is innervated by forebrain structures such as the shell of the nucleus accumbens (NAc) and ventral pallidum (VP) 43,56 which are activated by PF (Figure 2A), it is plausible that the aforementioned areas increase LHA neuron excitability and dampen competing inhibitory Gal-ergic inputs (from a presently unknown brain area) to OX neurons.…”

“…The model postulates that besides positive emotional, cognitive and hedonic drivers, PF overeating results from a disruption of the ability of leptin to influence communication between Gal and OX neurons since activation of Gal2R in the LHA reduces PF consumption (see Figure 5C-E) | 11 of 16 LEIDMAA Et AL feeding behaviour, which is essential for survival, depends on in-built fail-safe mechanisms, rather than simple homeostatic reflexes. [58][59][60] Rather, it highlights input-output relationships between the LHA and periphery as well as brain areas that receive and process sensory information 4,43,61 ; among these, the central amygdala and VTA, both innervated by OX-ergic neurons in the LHA, contribute to flavour and reward learning. Thus, the hypophagic response to just a single hormone (eg leptin) may be small and probabilistic.…”

“…Recent work shows that leptin reduces the strength of presynaptic excitatory inputs to OX neurons that project to the VTA, an effect blunted in diet-induced obesity. 4 Given that the LHA is innervated by forebrain structures such as the shell of the nucleus accumbens (NAc) and ventral pallidum (VP) 43,56 which are activated by PF (Figure 2A), it is plausible that the aforementioned areas increase LHA neuron excitability and dampen competing inhibitory Gal-ergic inputs (from a presently unknown brain area) to OX neurons. At the same time, because OX neurons are known to integrate complex and even counteracting metabolic cues, 19,43 a role for other competing influences on OX neurons cannot be excluded.…”

“…The model shown in Figure 7 is necessarily simple -it does not include all of the proposed molecular players and switches through which PF may modulate leptin signalling and actions in the hypothalamus. [58][59][60] Rather, it highlights input-output relationships between the LHA and periphery as well as brain areas that receive and process sensory information 4,43,61 ; among these, the central amygdala and VTA, both innervated by OX-ergic neurons in the LHA, contribute to flavour and reward learning. 4,62-66…”

“…The abundance and convenience of energy-rich foods with high hedonic value poses a homeostatic challenge for modern humans and predisposes them to obesity and associated cardiometabolic and psychiatric diseases. 1 While the maladaptive peripheral and central responses to chronic overeating have been extensively explored, [2][3][4] present knowledge of the proximal neurobiological mechanisms that initiate overeating is poor. In light of the "hedonia hypothesis of obesity" that posits that foods imbued with pleasurable signals override (and/or reset) homeostatic set-points, 5 we here aimed at identifying mechanisms that may counter anorexigenic signalling when lean mice encounter hedonic foods.…”