Leptin Action on GABAergic Neurons Prevents Obesity and Reduces Inhibitory Tone to POMC Neurons

Abstract

SUMMARY Leptin acts in the brain to prevent obesity. The underlying neurocircuitry responsible for this is poorly understood, in part due to incomplete knowledge regarding first order, leptin-responsive neurons. To address this, we and others have been removing leptin receptors from candidate first order neurons. While functionally relevant neurons have been identified, the observed effects have been small suggesting that most first order neurons remain unidentified. Here we take an alternative approach and test whether first order neurons are inhibitory (GABAergic, VGAT+) or excitatory (glutamatergic, VGLUT2+). Remarkably, the vast majority of leptin’s anti-obesity effects are mediated by GABAergic neurons; glutamatergic neurons play only a minor role. Leptin, working directly on presynaptic GABAergic neurons, many of which appear not to express AgRP, reduces inhibitory tone to postsynaptic POMC neurons. As POMC neurons prevent obesity, their disinhibition by leptin action on presynaptic GABAergic neurons likely mediates, at least in part, leptin’s anti-obesity effects.

Deficiency of the RIIβ subunit of PKA affects locomotor activity and energy homeostasis in distinct neuronal populations

“…The Vgat-ires-Cre triggered reexpression of RIIβ in the DMH, ARC, and LH, but not the VMH and PVH regions of the hypothalamus (Fig. 6A), as expected, because these latter areas are primarily composed of glutamatergic neurons (23,24). Reexpression of RIIβ is also strong in the striatum (Fig.…”

“…The RIIβ reexpression studies described above implicate the hypothalamus as the site of the lean phenotype, but our efforts to pinpoint a specific cell type were unsuccessful. A recent study using a Vgat-ires-Cre to specifically eliminate the LepR demonstrated that LepRs in GABAergic inhibitory neurons are the key regulators of body weight (23). Using this Cre-expressing mouse line, we have reexpressed RIIβ only in GABAergic neurons to test whether this subset of neurons is responsible for the lean and hyperactive phenotypes of RIIβ KO mice.…”

Distinct neural mechanisms for the control of thirst and salt appetite in the subfornical organ

“…In addition to the mice as described in chapter II, Slc17a6-ires-Cre (Vglut2-Cre) (Vong et al, 2011) (Jackson Labs stock 016963), Gad1-GFP (Δneo) (GAD67-GFP) (Tamamaki et al, 2003), and Slc32a1-ires-Cre (Vgat-Cre) (Vong et al, 2011) (Jackson Labs stock 016962) mice were used. In some optogenetic experiments, multiple behavioral tests were conducted in the same group of mice.…”

New Clues and New Questions regarding Leptin and Brain Metabolism

“…Less is known about how leptin affects other pathways including the GABAergic, glutamatergic, and dopaminergic systems (Scherer and Buettner, 2011;Vong et al, 2011).…”

“…Understanding the dynamics and players involved in hypothalamic metabolism in obesity has been an elusive goal despite many decades of research, and is an intense area of current research (Koch et al, 2011;Scott et al, 2011;Vong et al, 2011;Williams and Schwartz, 2011). In the featured manuscript on neuroglial metabolic compartmentation underlying leptin deficiency in the obese ob/ob mice, Delgado et al (2011) used a multifaceted approach to study activity and metabolism in hypothalamic nuclei of control and ob/ob mice.…”