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Neutering is a significant risk factor for obesity in cats. The mechanisms that promote neuter-associated weight gain are not well understood but following neutering, acute changes in energy expenditure and energy consumption have been observed. Metabolic profiling GC-MS and UHPLC-MS-MS was used in a longitudinal study to identify changes associated with age, sexual development and neutering in male cats fed a nutritionally-complete dry diet to maintain an ideal body condition score.
Age was the primary driver of variance in the plasma metabolome, including a developmental change independent of neuter group between 19 and 21 weeks in lysolipids and fatty acid amides. Pathway Enrichment Analysis also identified significant effects in 20 pathways, dominated by amino acid, sterol and fatty acid metabolism. Most changes were interpretable within the context of male sexual development, and changed following neutering in the CN group.
Felinine metabolism in CN cats was the most significantly altered pathway, increasing during sexual development and decreasing acutely following neutering.
Felinine is a testosterone-regulated, felid-specific glutathione derivative secreted in urine. Alterations in tryptophan, histidine and tocopherol metabolism observed in peripubertal cats may be to support physiological functions of glutathione following diversion of S-amino acids for urinary felinine secretion. Neutering is recommended for cats by veterinarians for population welfare reasons as it reduces unwanted pregnancies, but it also has benefits for the individual, including a reduction in the risk of certain reproductive disorders and diseases [ 1 , 2 ] and unwanted aggressive behaviours [ 3 ].
However, these have to be balanced against the management of some potentially undesirable consequences for the individual as neutering is a significant risk factor for obesity, which is itself associated with multiple health concerns diabetes, dyslipidemia and osteoarthritis [ 4 , 5 ].
In cats, evidence indicates that an acute post-neuter increased food intake in ad libitum environments is a major driver of increased percentage body fat and body weight that persist through life and may have health consequences. Offering options to prevent weight gain associated with neutering requires an understanding of the different factors that may underpin the post-neuter dysregulation of self-regulated food intake. The impact of neutering on weight is considered a consequence of two factors, a reduction in energy expenditure and increased consumption when fed ad libitum [ 8 — 15 ].
Similarly, post-neuter changes in energy expenditure have also been suggested in other species [ 11 ]. Evidence also exists that cats consume more if fed ad libitum [ 12 , 13 ].
Peptides regulating hunger and satiety feeding behaviours have been investigated in cats [ 10 , 14 , 15 ], but using different methods and in cats of different ages, under different feeding regimens and sampled over different time periods. Oestrogen is a major regulator of energy intake in cats, and injection of estradiol E2 following neutering is sufficient to prevent increased food intake and weight gain in both males and females [ 16 , 17 ].
Whilst loss of oestrogen-dependent energy regulation may be the primary cause of energy imbalance following neutering in females, neutering is also a predisposition for obesity in male cats and the mechanism is less clear. If sex hormones are responsible for changing energy regulation and intake behaviour, it is possible that neutering before sexual development occurs would avoid this regulatory dominance and subsequent acute response in the post-neuter phase.
Traditionally, cats are neutered around 6 to 7 months old [ 18 ], but early neutering before or at 4 months old is commonly performed in the US for animal welfare population control [ 19 ] and also appears to be safe [ 20 ].
However, some evidence indicate that regardless of the age at which it is performed, neutering is a significant risk factor for obesity [ 14 , 21 , 22 ]. Many studies investigating the effect of neutering use adult cats and allow ad libitum feeding.
However, most cats are neutered whilst under one year old and still growing. The current NRC feeding guidelines for kittens NRC are considered to be inappropriately high and feeding to an ideal body condition score is recommended as a more appropriate method of feeding kittens [ 13 ]. The current study aimed to establish the total energy requirements to maintain an ideal body condition score during growth up to one year old in male kittens.
The impact of neutering was investigated and the study included a number of physiological measures such as intake, body weight, body composition, spontaneous physical activity, clinical biochemistry. As kittens were fed to maintain an ideal body condition score, the opportunity for excessive weight and fat mass gain was reduced, which enabled factors that may drive acute neuter-dependent changes to be assessed for example gut hormone, faecal microbiome and plasma metabolic profile analysis.
The metabolic profiling data analysis and interpretation for male cats in that study is reported in detail here. The metabolic profiling study reported here refers to a cohort of 16 domestic short-haired male kittens from 13 litters recruited on to a trial feeding a commercially available diet, that measured food intake, body weight, body condition score, activity levels, hunger and satiety hormones, faecal microbiome, diet digestibility and metabolic profiles at different stages through to one year old.
Kittens had free access to fresh water and were fed from a single batch of a nutritionally complete [ 23 ], commercial dry diet formulated to support kittens through growth [Royal Canin Kitten, Aimargues, France] for a minimum of 4 weeks before the first sample.
Kittens were individually fed to maintain an ideal body condition score based on the S. Kittens were housed in a single social group and allocated to two groups based on age when they were to be neutered, with only one litter member represented in each group. Neutering was performed as part of normal veterinary practice at WALTHAM and occurred at one of two time points, defined as early EN , at 19 weeks old and as conventional CN , at 31 weeks old, with 8 kittens in each respective group.
One kitten was removed from this study CN group as we were unable to obtain a blood sample in accordance with our welfare policy. Food intake g was measured daily and body weight kg and body condition score 7-point scale weekly. Spontaneous physical activity levels were assessed average count for 24 hour periods over three consecutive days using Actical devices Philips Respironics when cats were 19, 25, 31, 37, 43 and 52 weeks old. Metabolite profiling was provided by Metabolon Inc.
Fractionation and derivisation of samples and detection technologies have been reported previously [ 25 — 27 ]. These randomly distributed samples included extracts of a pool of well-characterized human plasma, extracts of a pool created from a small aliquot of all plasma samples note that this also includes plasma samples from a total of 43 kittens, including females and not reported here , and process blanks.
Data extraction, metabolite identification and metabolite quantification were undertaken using proprietary software. To enable statistical analysis in samples where metabolites were not detected, the minimum value of that metabolite that had been detected was imputed. Prior to analysis, all data were log 10 transformed. Each individual metabolite response S1 Table was analysed by linear mixed effects models LMM with neuter status, age and their interaction as fixed effects and cat as a random effect.
Models could not be fitted to six metabolites X, sucrose, atenolol, 2-oxindoleacetate, HEPE and 1,1-kestotetraose which were singular values e. Planned contrasts were performed comparing the following: The coefficients and variance-covariance matrix of each LMM were used, along with a normal approximation to the degrees of freedom, to calculate each comparison and their subsequent confidence intervals and p -values using simultaneous inference [ 28 , 29 ].
Statistical analyses were performed in R v 3. Data were log 10 transformed and standardised prior to analysis. Correlation coefficient analysis was performed for both neuter groups across all time points. Permutation testing was then performed for each contrast to identify pathways designated by Metabolon Inc.
The number of metabolites in each pathway and the subset with a significant contrast were calculated. One thousand random subsets of the number of significant metabolites were then taken to represent random significant metabolites and the number found in each pathway calculated.
The probability of a pathway containing more significant metabolite groups than would be expected by chance was calculated as the percentage of subsets where the random number in each pathway was greater or equal to the number of significant metabolites in each pathway. Epidemiological data indicated that, irrespective of neuter age, neutering is associated with increased food intake and propensity for weight gain. This study showed no intrinsic effect of neutering on energy intake relative to metabolic body weight in male cats.
However, the increase in energy intake relative to metabolic body weight compared to the EN cats observed between weeks 3—10 post-procedure in CN cats is consistent with other post-neuter responses observed in adult male cats [ 15 ]. These data suggest that neutering males in the early stages of sexual development may reduce acute feeding behaviour changes. Peptide hormones ghrelin, GIP, insulin and leptin concentrations did not differ significantly between groups at any time point data not shown , nor did faecal genera [ 33 ].
Albeit from a small cohort, these data suggest that when fed to maintain an ideal body condition score, neutering males in the early stages of sexual development has minimal impact across a spectrum of physiological functions. Metabolic profiling detected metabolites, of which were consistently detectable in all samples.
To determine the main drivers of variance in the plasma metabolome, multivariate analysis was performed using Principal Component Analysis PCA Fig 1. Age was the primary driver of variance in the first two principal components PC , though differences between neuter groups, observable at week 31, indicated some effect of neutering. However, the groups converged within twelve weeks of neutering the CN group, indicating that neutering age had no persistent impact on the plasma metabolome.
PCA of plasma metabolome samples from males, labelled by neuter group and age, indicate that age is the primary driver of variance between samples. In mice, gene expression analysis over the pre-pubertal-to-early adult developmental phase identified changes indicative of the switch from liver growth to specialised functions, such as bile production [ 34 ]. The decline in FA amides and acylGPCs here may be due to a similar acute developmental switch and is supported by previously reported differences in lipid metabolism between kittens of 20 weeks and 32 weeks old [ 35 ].
Changes in the average abundance of metabolites for which significant changes were observed between 19 and 21 weeks of age in males in both neuter groups, CN red and EN black , all of which were present in only 2 lipid metabolite subgroups see Table 2 for details. All metabolites belonged to two groups of lipids, fatty acid amides and glycerophosphocholine lysolipids.
Neutering, at any age, is reported to be associated with an increased risk of weight gain. To determine if neutering had a similar effect on metabolism irrespective of age, the metabolic profiles were analysed between the samples from the final pre-neuter time point and the first post-neuter time point two weeks later.
Only retinoate and transhydroxyproline changed in both EN and CN cats 1. Univariate analysis determined metabolites differing between groups at each comparable time point Table 2.
No significant differences were observed between the groups at 19 weeks old, when both were entire, nor at 21 weeks, indicating no acute detectable effect on the metabolome 2 weeks post-neutering. Eight metabolites differed between the groups at week 25, 33 at week 31 and 19 within 2 weeks of neutering in the CN group. Only 2 metabolites were significantly different 12 weeks post-operation week These univariate analyses are consistent with PCA and indicate that despite dynamic differences as a consequence of sexual development in the CN cats, there is little evidence to suggest the age when neutered 19 and 31 weeks old resulted in long-term effects on the plasma metabolome.
A further 16 unknown metabolites also met this significance cut-off, with all differences between 25—37 weeks and 11 significantly different at week The list is sorted by decreasing significance values at week 31, the time point with the largest number of significant differences. Metabolites in bold belong to metabolic subpathways found to have more significant metabolite groups than would be expected by chance between the two neuter groups at some time point see text.
An objective was to detect changes in fasted plasma samples as a consequence of neutering that may implicate a fundamental change in metabolism responsible in initiating previously observed post-neuter weight gain in cats [ 8 , 10 , 13 ]. No substantial evidence was found to suggest that neutering per se causes a change in metabolic regulation. Instead, evidence indicated that the primary differentiating driver was sexual development and changes subsequent to neutering in the CN cats.
To characterise the consequences of neutering following sexual development, metabolites that changed in the CN group from 31 weeks old and subsequent sampling points were identified S1 Table.
Many of the 85 metabolites were involved in similar areas of metabolism 39 metabolic pathways , with changes predominantly related to amino acid and lipid metabolism. To gain a broader understanding of the pathways that were most affected over time within and between groups, a Pathway Set Enrichment analysis was undertaken Table 3. These results are described below. Twenty pathways were found to contain more significant metabolite groups than would be expected by chance, for contrasts between groups and within groups, ranked to be consistent with the metabolites in Table 2.
These all increased in sexually maturing cats, and following neutering they decreased, until similar to EN cats by 12 weeks post-neuter Fig 3a—3d , Table 2. Changes in the average abundance of metabolites of the felinine pathway and a related dipeptide in the two groups CN red and EN black. Felinine is found predominantly in the urine of sexually mature male cats, and may have a role in territorial marking and conspecific recognition [ 36 ].
As felinine and N-acetyl felinine were not detected in serum previously [ 37 ], their identification in this study may result from different methodologies and study design. Urinary felinine is detected from 2. Urinary felinine is regulated by testosterone, with neutered male cats producing approximately 3—5 fold less than entire males [ 36 ] and increasing urinary felinine in response to testosterone supplementation [ 38 ].
Whilst testosterone was not assayed here, the felinine-related data were consistent with previous reports where testosterone was detected by 5 months of age and neutering resulted in a parallel fall in plasma testosterone and urinary felinine [ 38 ]. The similar profiles from metabolites within the same pathway, interpretable with known physiological changes in sexual development in the cat over a prolonged period, provide confidence in interpretability of metabolite pools in fasted plasma.
Furthermore, these and two other tryptophan-related metabolites indoleacetate and 3-indoxyl sulfate differed in CN cats between 31 and 43 weeks S1 Table. These are consistent with sexual development impacting tryptophan metabolism and neutering reverting the effect.
Changes in tryptophan metabolism during human adolescence have been identified [ 39 ] and in kynurenine with castration in rats [ 40 ].
AG Heinrichs | Universitätsklinikum Freiburg
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