Leptin is an adipocytokine that circulates in proportion to body fat to signal the repletion of long-term energy stores. Leptin acts via its receptor, LepRb, on specialized neuronal populations in ...the brain (mainly in the hypothalamus and brainstem) to alter motivation and satiety, as well as to permit energy expenditure and appropriate glucose homeostasis. Decreased leptin, as with prolonged caloric restriction, promotes a powerful orexigenic signal, decreases energy use via a number of neuroendocrine and autonomic axes, and disrupts glucose homeostasis. Here, we review what is known about cellular leptin action and focus on the roles for specific populations of LepRb-expressing neurons for leptin action.
High-fat diet (HFD) is associated with Alzheimer's disease (AD) and type 2 diabetes risk, which share features such as insulin resistance and amylin deposition. We examined gene expression associated ...with astrocytes and microglia since dysfunction of these cell types is implicated in AD pathogenesis. We hypothesize gene expression changes in disease-associated astrocytes (DAA), disease-associated microglia and human Alzheimer's microglia exist in diabetic and obese individuals before AD development. By analyzing bulk RNA-sequencing (RNA-seq) data generated from brains of mice fed HFD and humans with AD, 11 overlapping AD-associated differentially expressed genes were identified, including Kcnj2, C4b and Ddr1, which are upregulated in response to both HFD and AD. Analysis of single cell RNA-seq (scRNA-seq) data indicated C4b is astrocyte specific. Spatial transcriptomics (ST) revealed C4b colocalizes with Gfad, a known astrocyte marker, and the colocalization of C4b expressing cells with Gad2 expressing cells, i.e., GABAergic neurons, in mouse brain. There also exists a positive correlation between C4b and Gad2 expression in ST indicating a potential interaction between DAA and GABAergic neurons. These findings provide novel links between the pathogenesis of obesity, diabetes and AD and identify C4b as a potential early marker for AD in obese or diabetic individuals.
Background Stress-related disorders (e.g., depression) are associated with hypothalamic-pituitary-adrenocortical axis dysregulation and prefrontal cortex (PFC) dysfunction, suggesting a functional ...link between aberrant prefrontal corticosteroid signaling and mood regulation. Methods We used a virally mediated knockdown strategy (short hairpin RNA targeting the glucocorticoid receptor GR) to attenuate PFC GR signaling in the rat PFC. Adult male rats received bilateral microinjections of vector control or short hairpin RNA targeting the GR into the prelimbic ( n = 44) or infralimbic ( n = 52) cortices. Half of the animals from each injection group underwent chronic variable stress, and all were subjected to novel restraint. The first 2 days of chronic variable stress were used to assess depression- and anxiety-like behavior in the forced swim test and open field. Results The GR knockdown confined to the infralimbic PFC caused acute stress hyper-responsiveness, sensitization of stress responses after chronic variable stress, and induced depression-like behavior (increased immobility in the forced swim test). Knockdown of GR in the neighboring prelimbic PFC increased hypothalamic-pituitary-adrenocortical axis responses to acute stress and caused hyperlocomotion in the open field, but did not affect stress sensitization or helplessness behavior. Conclusions The data indicate a marked functional heterogeneity of glucocorticoid action in the PFC and highlight a prominent role for the infralimbic GR in appropriate stress adaptation, emotional control, and mood regulation.
Abstract The visible burrow system produces a distinct combination of psychological and metabolic stress on, primarily, subordinate individuals that results in pronounced physiologic and behavioral ...dysfunction. However, the mechanisms underlying the consequences of chronic subordination stress are largely unknown. The simplest mechanistic explanation is that adaptations within brain systems with overlapping functions of both psychological and metabolic control provide immediate benefits that result in lasting susceptibility to diseases, disorders, and increased mortality rates in subordinates. Circuits regulated by leptin adapt to fluctuating levels of energy storage, such that the loss of leptin action within leptin-regulated neurocircuitry results in dysfunction in physiologic and behavioral systems implicated in the consequences of chronic social subordination. Thus, leptin-regulated neurocircuitry may provide a window into understanding the consequences of social subordination stress. This review examines the neural systems of leptin physiology implicated in social subordination stress: energy balance, motivation, HPA axis, and glycemic control.
To understand hindbrain pathways involved in the control of food intake, we examined roles for calcitonin receptor (CALCR)-containing neurons in the NTS. Ablation of NTS Calcr abrogated the long-term ...suppression of food intake, but not aversive responses, by CALCR agonists. Similarly, activating CalcrNTS neurons decreased food intake and body weight but (unlike neighboring CckNTS cells) failed to promote aversion, revealing that CalcrNTS neurons mediate a non-aversive suppression of food intake. While both CalcrNTS and CckNTS neurons decreased feeding via projections to the PBN, CckNTS cells activated aversive CGRPPBN cells while CalcrNTS cells activated distinct non-CGRP PBN cells. Hence, CalcrNTS cells suppress feeding via non-aversive, non-CGRP PBN targets. Additionally, silencing CalcrNTS cells blunted food intake suppression by gut peptides and nutrients, increasing food intake and promoting obesity. Hence, CalcrNTS neurons define a hindbrain system that participates in physiological energy balance and suppresses food intake without activating aversive systems.
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•NTS Calcr mediates food intake suppression but not aversive responses to sCT•Activating NTS Calcr neurons non-aversively suppresses feeding•These neurons act via non-CGRP PBN neurons•These neurons control long-term energy balance, not just short-term feeding
While the hindbrain is often postulated to control only short-term parameters of feeding via circuits that mediate aversive responses when activated strongly, Cheng et al. have identified a hindbrain system that participates in the physiological control of energy balance and suppresses food intake without activating aversive systems or symptoms.
Late adolescent animals are more susceptible to the somatic, HPA axis, and neuropeptide effects of chronic stress.
Adolescent development is proposed to represent a time of increased susceptibility ...to stress. During adolescence, the brain demonstrates a high level of plasticity and can be positively or negatively affected by the environment. This study tests the hypothesis that adolescent development is a stage of enhanced vulnerability to chronic stress. Male Sprague-Dawley rats were exposed to our 14-d chronic variable stress (CVS) paradigm at three developmental stages: 1) early adolescence (35 d; age at initiation of CVS); 2) late adolescence (50 d); or 3) adulthood (80 d). We examined the effects of CVS on the following: 1) depression-like behavior; 2) somatic indices; 3) hypothalamic-pituitary-adrenal (HPA) axis activity; and 4) neuropeptide expression in the hypothalamus. Results show, regardless of age, CVS exposure: 1) decreased body weight; 2) increased adrenal size; 3) decreased fat weight; and 4) increased HPA response to stress. The somatic effects of CVS were exaggerated in late adolescent animals, and late adolescent animals were the only group where CVS decreased oxytocin expression and increased basal corticosterone. In response to CVS, adult animals increased immobility during the forced-swim test while early and late adolescent animals were resistant to the effects of chronic stress on depression-like behavior. Results show that adolescent animals were protected from the effect of chronic stress on depression-like behavior while late adolescent animals were more susceptible to the somatic, HPA axis, and neuropeptide effects of chronic stress. Thus, adolescent development is a unique window of vulnerabilities and protections to the effects of chronic stress.
Chronic stress induces presynaptic and postsynaptic modifications in the paraventricular nucleus of the hypothalamus that are consistent with enhanced excitatory hypothalamo‐pituitary‐adrenocortical ...(HPA) axis drive. The brain regions mediating these molecular modifications are not known. We hypothesized that chronic variable stress (CVS) tonically activates stress‐excitatory regions that interact with the paraventricular nucleus of the hypothalamus, culminating in stress facilitation. In order to identify chronically activated brain regions, ΔFosB, a documented marker of tonic neuronal activation, was assessed in known stress regulatory limbic and brainstem sites. Four experimental groups were included: CVS, repeated restraint (RR) (control for HPA habituation), animals weight‐matched (WM) to CVS animals (control for changes in circulating metabolic factors due to reduced weight gain), and non‐handled controls. CVS, (but not RR or WM) induced adrenal hypertrophy, indicating that sustained HPA axis drive only occurred in the CVS group. CVS (but not RR or WM) selectively increased the number of FosB/ΔFosB nuclei in the nucleus of the solitary tract, posterior hypothalamic nucleus, and both the infralimbic and prelimbic divisions of the medial prefrontal cortex, indicating an involvement of these regions in chronic drive of the HPA axis. Increases in FosB/ΔFosB‐immunoreactive cells were observed following both RR and CVS in the other regions (e.g. the dorsomedial hypothalamus), suggesting activation by both habituating and non‐habituating stress conditions. The data suggest that unpredictable stress uniquely activates interconnected cortical, hypothalamic, and brainstem nuclei, potentially revealing the existence of a recruited circuitry mediating chronic drive of brain stress effector systems.
Chronic variable stress (CVS) causes specific enhancement of delta‐FosB expression in select central regulatory circuits, including the prefrontal cortex, posterior hypothalamic nucleus and nucleus of the solitary tract. Delta‐FosB changes are not observed in a habituating stress regimen (repeated restraint), implying that CVS‐related changes are driven by recruitment of these key cortical, hypothalamic and hindbrain circuits.
Abstract
Body energy homeostasis results from balancing energy intake and energy expenditure. Central nervous system administration of pituitary adenylate cyclase activating polypeptide (PACAP) ...dramatically alters metabolic function, but the physiologic mechanism of this neuropeptide remains poorly defined. PACAP is expressed in the mediobasal hypothalamus (MBH), a brain area essential for energy balance. Ventromedial hypothalamic nucleus (VMN) neurons contain, by far, the largest and most dense population of PACAP in the medial hypothalamus. This region is involved in coordinating the sympathetic nervous system in response to metabolic cues in order to re-establish energy homeostasis. Additionally, the metabolic cue of leptin signaling in the VMN regulates PACAP expression. We hypothesized that PACAP may play a role in the various effector systems of energy homeostasis, and tested its role by using VMN-directed, but MBH encompassing, adeno-associated virus (AAVCre) injections to ablate Adcyap1 (gene coding for PACAP) in mice (Adcyap1MBHKO mice). Adcyap1MBHKO mice rapidly gained body weight and adiposity, becoming hyperinsulinemic and hyperglycemic. Adcyap1MBHKO mice exhibited decreased oxygen consumption (VO2), without changes in activity. These effects appear to be due at least in part to brown adipose tissue (BAT) dysfunction, and we show that PACAP-expressing cells in the MBH can stimulate BAT thermogenesis. While we observed disruption of glucose clearance during hyperinsulinemic/euglycemic clamp studies in obese Adcyap1MBHKO mice, these parameters were normal prior to the onset of obesity. Thus, MBH PACAP plays important roles in the regulation of metabolic rate and energy balance through multiple effector systems on multiple time scales, which highlight the diverse set of functions for PACAP in overall energy homeostasis.
Abstract
The adipocyte-derived hormone leptin acts via its receptor (LepRb) on central nervous system neurons to communicate the repletion of long-term energy stores, to decrease food intake, and to ...promote energy expenditure. We generated mice that express Cre recombinase from the calcitonin receptor (Calcr) locus (Calcrcre mice) to study Calcr-expressing LepRb (LepRbCalcr) neurons, which reside predominantly in the arcuate nucleus (ARC). Calcrcre-mediated ablation of LepRb in LepRbCalcrknockout (KO) mice caused hyperphagic obesity. Because LepRb-mediated transcriptional control plays a crucial role in leptin action, we used translating ribosome affinity purification followed by RNA sequencing to define the transcriptome of hypothalamic Calcr neurons, along with its alteration in LepRbCalcrKO mice. We found that ARC LepRbCalcr cells include neuropeptide Y (NPY)/agouti-related peptide (AgRP)/γ-aminobutyric acid (GABA) (“NAG”) cells as well as non-NAG cells that are distinct from pro-opiomelanocortin cells. Furthermore, although LepRbCalcrKO mice exhibited dysregulated expression of several genes involved in energy balance, neither the expression of Agrp and Npy nor the activity of NAG cells was altered in vivo. Thus, although direct leptin action via LepRbCalcr cells plays an important role in leptin action, our data also suggest that leptin indirectly, as well as directly, regulates these cells.
Leptin acts via calcitonin receptor‒expressing hypothalamic neurons to control feeding and energy balance.
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