A considerable body of evidence links diminished brain-derived neurotrophic factor (BDNF) signaling to energy balance dysregulation and severe obesity in humans and rodents. Because BDNF exhibits ...broad neurotrophic properties, the underpinnings of these effects and its true role in the central regulation of food intake remain topics of debate in the field. Here, I discuss recent evidence supporting a critical role for this neurotrophin in physiological mechanisms regulating nutrient intake and body weight in the mature brain. They include reports of functional interactions of BDNF with central anorexigenic and orexigenic signaling pathways and evidence of recognized appetite hormones exerting neurotrophic effects similar to those of BDNF.
The global rise in obesity and related health issues, such as type 2 diabetes and cardiovascular disease, is alarming. Gaining a deeper insight into the central neural pathways and mechanisms that ...regulate energy and glucose homeostasis is crucial for developing effective interventions to combat this debilitating condition. A significant body of evidence from studies in humans and rodents indicates that brain-derived neurotrophic factor (BDNF) signaling plays a key role in regulating feeding, energy expenditure, and glycemic control. BDNF is a highly conserved neurotrophin that signals via the tropomyosin-related kinase B (TrkB) receptor to facilitate neuronal survival, differentiation, and synaptic plasticity and function. Recent studies have shed light on the mechanisms through which BDNF influences energy and glucose balance. This review will cover our current understanding of the brain regions, neural circuits, and cellular and molecular mechanisms underlying the metabolic actions of BDNF and TrkB.
Brain-derived neurotrophic factor (BDNF) is involved in synaptic plasticity, neuronal differentiation and survival of neurons. Observations of decreased serum BDNF levels in patients with ...neuropsychiatric disorders have highlighted the potential of BDNF as a biomarker, but so far there have been no studies directly comparing blood BDNF levels to brain BDNF levels in different species. We examined blood, serum, plasma and brain-tissue BDNF levels in three different mammalian species: rat, pig, and mouse, using an ELISA method. As a control, we included an analysis of blood and brain tissue from conditional BDNF knockout mice and their wild-type littermates. Whereas BDNF could readily be measured in rat blood, plasma and brain tissue, it was undetectable in mouse blood. In pigs, whole-blood levels of BDNF could not be measured with a commercially available ELISA kit, but pig plasma BDNF levels (mean 994±186 pg/ml) were comparable to previously reported values in humans. We demonstrated positive correlations between whole-blood BDNF levels and hippocampal BDNF levels in rats (r2=0.44, p=0.025) and between plasma BDNF and hippocampal BDNF in pigs (r2=0.41, p=0.025). Moreover, we found a significant positive correlation between frontal cortex and hippocampal BDNF levels in mice (r2=0.81, p=0.0139). Our data support the view that measures of blood and plasma BDNF levels reflect brain-tissue BDNF levels.
The prevalence of obesity and its associated medical complications, including type 2 diabetes and cardiovascular disease, continues to rise globally. Lifestyle changes in the last decades have ...greatly contributed to the current obesity trends. However, inheritable biological factors that disrupt the tightly regulated equilibrium between caloric intake and energy expenditure also appear to play a critical part. Mounting evidence obtained from human and rodent studies suggests that perturbed brain-derived neurotrophic factor (BDNF) signaling in appetite-regulating centers in the brain might be a culprit. Here, we review findings that inform the critical roles of BDNF and its receptor TrkB in energy balance and reward centers of the brain impacting feeding behavior and body weight.
Mice experiencing repeated aggression develop a long-lasting aversion to social contact, which can be normalized by chronic, but not acute, administration of antidepressant. Using viral-mediated, ...mesolimbic dopamine pathway-specific knockdown of brain-derived neurotrophic factor (BDNF), we showed that BDNF is required for the development of this experience-dependent social aversion. Gene profiling in the nucleus accumbens indicates that local knockdown of BDNF obliterates most of the effects of repeated aggression on gene expression within this circuit, with similar effects being produced by chronic treatment with antidepressant. These results establish an essential role for BDNF in mediating long-term neural and behavioral plasticity in response to aversive social experiences.
Brain-derived neurotrophic factor (BDNF) and its receptor, TrkB, play prominent roles in food intake regulation through central mechanisms. However, the neural circuits underlying their anorexigenic ...effects remain largely unknown. We showed previously that selective BDNF depletion in the ventromedial hypothalamus (VMH) of mice resulted in hyperphagic behavior and obesity. Here, we sought to ascertain whether its regulatory effects involved the mesolimbic dopamine system, which mediates motivated and reward-seeking behaviors including consumption of palatable food. We found that expression of BDNF and TrkB mRNA in the ventral tegmental area (VTA) of wild-type mice was influenced by consumption of palatable, high-fat food (HFF). Moreover, amperometric recordings in brain slices of mice depleted of central BDNF uncovered marked deficits in evoked release of dopamine in the nucleus accumbens (NAc) shell and dorsal striatum but normal secretion in the NAc core. Mutant mice also exhibited dramatic increases in HFF consumption, which were exacerbated when access to HFF was restricted. However, mutants displayed enhanced responses to D(1) receptor agonist administration, which normalized their intake of HFF in a 4 h food intake test. Finally, in contrast to deletion of Bdnf in the VMH of mice, which resulted in increased intake of standard chow, BDNF depletion in the VTA elicited excessive intake of HFF but not of standard chow and increased body weights under HFF conditions. Our findings indicate that the effects of BDNF on eating behavior are neural substrate-dependent and that BDNF influences hedonic feeding via positive modulation of the mesolimbic dopamine system.
A brief burst-suppressing isoflurane anesthesia has been shown to rapidly alleviate symptoms of depression in a subset of patients, but the neurobiological basis of these observations remains ...obscure. We show that a single isoflurane anesthesia produces antidepressant-like behavioural effects in the learned helplessness paradigm and regulates molecular events implicated in the mechanism of action of rapid-acting antidepressant ketamine: activation of brain-derived neurotrophic factor (BDNF) receptor TrkB, facilitation of mammalian target of rapamycin (mTOR) signaling pathway and inhibition of glycogen synthase kinase 3β (GSK3β). Moreover, isoflurane affected neuronal plasticity by facilitating long-term potentiation in the hippocampus. We also found that isoflurane increased activity of the parvalbumin interneurons, and facilitated GABAergic transmission in wild type mice but not in transgenic mice with reduced TrkB expression in parvalbumin interneurons. Our findings strengthen the role of TrkB signaling in the antidepressant responses and encourage further evaluation of isoflurane as a rapid-acting antidepressant devoid of the psychotomimetic effects and abuse potential of ketamine.
Antidepressant drugs (ADs) have been shown to activate BDNF (brain-derived neurotrophic factor) receptor TrkB in the rodent brain but the mechanism underlying this phenomenon remains unclear. ADs act ...as monoamine reuptake inhibitors and after prolonged treatments regulate brain bdnf mRNA levels indicating that monoamine-BDNF signaling regulate AD-induced TrkB activation in vivo. However, recent findings demonstrate that Trk receptors can be transactivated independently of their neurotrophin ligands.
In this study we examined the role of BDNF, TrkB kinase activity and monoamine reuptake in the AD-induced TrkB activation in vivo and in vitro by employing several transgenic mouse models, cultured neurons and TrkB-expressing cell lines.
Using a chemical-genetic TrkB(F616A) mutant and TrkB overexpressing mice, we demonstrate that ADs specifically activate both the maturely and immaturely glycosylated forms of TrkB receptors in the brain in a TrkB kinase dependent manner. However, the tricyclic AD imipramine readily induced the phosphorylation of TrkB receptors in conditional bdnf⁻/⁻ knock-out mice (132.4±8.5% of control; P = 0.01), indicating that BDNF is not required for the TrkB activation. Moreover, using serotonin transporter (SERT) deficient mice and chemical lesions of monoaminergic neurons we show that neither a functional SERT nor monoamines are required for the TrkB phosphorylation response induced by the serotonin selective reuptake inhibitors fluoxetine or citalopram, or norepinephrine selective reuptake inhibitor reboxetine. However, neither ADs nor monoamine transmitters activated TrkB in cultured neurons or cell lines expressing TrkB receptors, arguing that ADs do not directly bind to TrkB.
The present findings suggest that ADs transactivate brain TrkB receptors independently of BDNF and monoamine reuptake blockade and emphasize the need of an intact tissue context for the ability of ADs to induce TrkB activity in brain.
Adiponectin (APN), the most abundant adipocyte-secreted adipokine, regulates energy homeostasis and exerts well-characterized insulin-sensitizing properties. The peripheral or central effects of APN ...regulating bone metabolism are beginning to be explored but are still not clearly understood. In the present study, we found that APN-knockout (APN-KO) mice fed a normal diet exhibited decreased trabecular structure and mineralization and increased bone marrow adiposity compared with wild-type (WT) mice. APN intracerebroventricular infusions decreased uncoupling protein 1 (UCP1) expression in brown adipose tissue, epinephrine and norepinephrine serum levels, and osteoclast numbers, whereas osteoblast osteogenic marker expression and trabecular bone mass increased in APN-KO and WT mice. In addition, centrally administered APN increased hypothalamic tryptophan hydroxylase 2 (TPH2), cocaine- and amphetamine-regulated transcript (CART), and 5-hydroxytryptamine (serotonin) receptor 2C (Htr2C) expressions but decreased hypothalamic cannabinoid receptor-1 expression. Treatment of immortalized mouse neurons with APN demonstrated that APN-mediated effects on TPH2, CART, and Htr2C expression levels were abolished by downregulating adaptor protein containing pleckstrin homology domain, phosphotyrosine domain, and leucine zipper motif (APPL)-1 expression. Pharmacological increase in sympathetic activity stimulated adipogenic differentiation of bone marrow stromal cells (BMSC) and reversed APN-induced expression of the lysine-specific demethylases involved in regulating their commitment to the osteoblastic lineage. In conclusion, we found that APN regulates bone metabolism via central and peripheral mechanisms to decrease sympathetic tone, inhibit osteoclastic differentiation, and promote osteoblastic commitment of BMSC.
Brain-derived neurotrophic factor has been associated previously
with the regulation of food intake. To help elucidate the role of this
neurotrophin in weight regulation, we have generated ...conditional
mutants in which brain-derived neurotrophic factor has been eliminated
from the brain after birth through the use of the cre-loxP
recombination system. Brain-derived neurotrophic factor conditional
mutants were hyperactive after exposure to stressors and had higher
levels of anxiety when evaluated in the light/dark exploration test.
They also had mature onset obesity characterized by a dramatic
80–150% increase in body weight, increased linear growth, and
elevated serum levels of leptin, insulin, glucose, and cholesterol. In
addition, the mutants had an abnormal starvation response and elevated
basal levels of POMC, an anorexigenic factor and the precursor forα
-MSH. Our results demonstrate that brain derived neurotrophic factor
has an essential maintenance function in the regulation of
anxiety-related behavior and in food intake through central mediators
in both the basal and fasted state.
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