Consumption of dietary fat causes loss of olfactory sensory neurons and associated circuitry that is not mitigated by voluntary exercise in mice

Chelette, Brandon M.; Loeven, Ashley M; Gatlin, Destinee N; Conde, Daniel R. Landi; Huffstetler, Carley; Qi, Meizhu; Fadool, James M.

doi:10.1113/jp282112

Cited by 12 publications

(15 citation statements)

References 82 publications

(203 reference statements)

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“…Olfactory cues play a key role in food consumption, including enhancing appetite and promoting food preparatory activities like salivation (Boone et al., 2021; Peris‐Sampedro et al., 2021; Rolls, 2005; Yeomans, 2006). Altered metabolic states such as fasting or obesity can drive changes in olfactory sensory processing, anatomy, and perception (Chelette et al., 2021; Fardone et al., 2019; Hanci & Altun, 2016; Julliard et al., 2017; Kolling & Fadool, 2020; Palouzier‐Paulignan et al., 2012; Thiebaud et al., 2014; Vogt et al., 2021; Wu et al., 2020). Understanding the relationship between neural processing and an organism's energy state is critical to understanding metabolic disorders such as obesity in which this relationship is disrupted.…”

Section: Introductionmentioning

confidence: 99%

An anatomically distinct subpopulation of orexin neurons project from the lateral hypothalamus to the olfactory bulb

Fadool

Storace

2023

J of Comparative Neurology

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Olfactory cues play a key role in natural behaviors such as finding food, finding mates, and avoiding predators. In principle, the ability of the olfactory system to carry out these perceptual functions would be facilitated by signaling related to an organism's physiological state. One candidate pathway includes a direct projection from the hypothalamus to the main olfactory bulb, the first stage of olfactory sensory processing. The pathway from the hypothalamus to the main olfactory bulb is thought to include neurons that express the neuropeptide orexin, although the proportion that is orexinergic remains unknown. A current model proposes that the orexin population is heterogeneous, yet it remains unknown whether the proportion that innervates the main olfactory bulb reflects a distinct subpopulation of the orexin population. Herein, we carried out combined retrograde tract tracing with immunohistochemistry for orexin‐A in the mouse to define the proportion of hypothalamic input to the main olfactory bulb that is orexinergic and to determine what fraction of the orexin‐A population innervates the bulb. The numbers and spatial positions of all retrogradely labeled neurons and all the orexin‐A‐expressing neurons were quantified in sequential sections through the hypothalamus. Retrogradely labeled neurons were found in the ipsilateral hypothalamus, of which 22% expressed orexin‐A. The retrogradely labeled neurons that did and did not express orexin‐A could be anatomically distinguished based on their spatial position and cell body area. Remarkably, only 7% of all the orexin‐A neurons were retrogradely labeled, suggesting that only a small fraction of the orexin‐A population directly innervate the main olfactory bulb. These neurons spatially overlapped with the orexin‐A neurons that did not innervate the bulb, although the two cell populations were differentiated based on cell body area. Overall, these results support a model in which olfactory sensory processing is influenced by orexinergic feedback at the first synapse in the olfactory processing pathway.

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Section: Introductionmentioning

confidence: 99%

An anatomically distinct subpopulation of orexin neurons project from the lateral hypothalamus to the olfactory bulb

Fadool

Storace

2023

J of Comparative Neurology

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“…11B, two-way mixed RM ANOVA, genotype F (1,15) = 0.1733, p = 0.6831). The lack of DIO in female mice has also been observed in C57BL6/J strains, so this was not unexpected (Chelette et al, 2022). Because increases in body weight can cause changes in glucose homeostasis and adipose deposition, we next examined these metrics that could indicate a prediabetic state.…”

Section: Crispr Mice Have Improved Metabolic Healthmentioning

confidence: 81%

“…Mice were metabolically profiled using indirect calorimetry. Mice were housed in Comprehensive Laboratory Animal Monitoring System (CLAMS) cages (Columbus Instruments; RRID:SCR_016718) to determine oxygen consumption (VO 2 ; ml/kg/min), respiratory exchange ratio (RER; VO 2 /VCO 2 ), EE (kcal/h; Lusk and Bois, 1924), locomotor activity, and ingestive behavior (caloric and water consumption) as previously performed (Bell and Fadool, 2017;Fadool and Kolling, 2020;Chelette et al, 2022). Mice had ad libitum access to food and water in overhead feeders attached to electronic balances that could detect both disturbance and decrease in mass.…”

Section: Metabolic Assessmentsmentioning

confidence: 99%

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Modulating the Excitability of Olfactory Output Neurons Affects Whole-Body Metabolism

et al. 2022

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Metabolic state can alter olfactory sensitivity, but it is unknown whether the activity of the olfactory bulb (OB) may fine tune metabolic homeostasis. Our objective was to use CRISPR gene editing in male and female mice to enhance the excitability of mitral/tufted projection neurons (M/TCs) of the OB to test for improved metabolic health. Ex vivo slice recordings of MCs in CRISPR mice confirmed increased excitability due the targeted loss of Kv1.3 channels, which resulted in a less negative resting membrane potential (RMP), enhanced action potential (AP) firing, and insensitivity to the selective channel blocker margatoxin (MgTx). CRISPR mice exhibited enhanced odor discrimination using a habituation/dishabituation paradigm. CRISPR mice were challenged for 25 weeks with a moderately high-fat (MHF) diet, and compared with littermate controls, male mice were resistance to diet-induced obesity (DIO). Female mice did not exhibit DIO. CRISPR male mice gained less body weight, accumulated less white adipose tissue, cleared a glucose challenge more quickly, and had less serum leptin and liver triglycerides. CRISPR male mice consumed equivalent calories as control littermates, and had unaltered energy expenditure (EE) and locomotor activity, but used more fats for metabolic substrate over that of carbohydrates. Counter to CRISPR-engineered mice, by using chemogenetics to decrease M/TC excitability in male mice, activation of inhibitory designer receptors exclusively activated by designer drugs (DREADDs) caused a decrease in odor discrimination, and resulted in a metabolic profile that was obesogenic, mice had reduced EE and oxygen consumption (VO 2 ). We conclude that the activity of M/TC projection neurons canonically carries olfactory information and simultaneously can regulate whole-body metabolism.

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“…In the current issue of The Journal of Physiology , Chelette and coworkers (2022) have examined this hypothesis in detail and provided compelling evidence that excess fat in the diet rather than the development of obesity is the cause for loss of OSNs and associated projections to the OB. To decouple diet‐induced obesity from dietary fat consumption, the authors developed a sophisticated pair‐feeding method that allowed feeding a moderately high‐fat (MHF) diet while keeping the total calories the same as in a nutrient‐balanced (but lower fat) control diet.…”

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confidence: 99%

Diet‐induced disruption of the olfactory system: not only obesity is to blame

Manzini

2022

The Journal of Physiology

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Consumption of dietary fat causes loss of olfactory sensory neurons and associated circuitry that is not mitigated by voluntary exercise in mice

Abstract: support-information-section).

Cited by 12 publications

References 82 publications

An anatomically distinct subpopulation of orexin neurons project from the lateral hypothalamus to the olfactory bulb

An anatomically distinct subpopulation of orexin neurons project from the lateral hypothalamus to the olfactory bulb

Modulating the Excitability of Olfactory Output Neurons Affects Whole-Body Metabolism

Diet‐induced disruption of the olfactory system: not only obesity is to blame

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