The correction of disturbances of energy homeostasis induced by intensive lactogenesis is a major challenge for the physiology of dairy cows. A lower feed intake at this time intensifies NEB and increases lipolysis [
4,
19]. Though a considerable portion of NEFA in cows is derived from the diet, Gross et al. (2013) [
4] indicated that the intensity of daily production also has a major impact. In their opinion, the rate of change in the NEB and triglycerides, including NEFA, released from the adipocytes increases up to the peak of lactation, thus increasing the NEFA level. The consequence of this is of the inability of liver to completely use acetyl CoA from the beta oxidation of NEFA for gluconeogenesis because other intermediates of the Krebs cycle are limited for the excessive load of acetyl CoA. Finally, this situation may be conducive to the generation of excess BHBA in the liver and affects the further course of lactation [
13,
20]. In a study by Knob et al. (2021) [
6], the BCS of Simmental cows was, on average, 1 point higher than that of Holstein cows during lactation. As in the present study, Knob et al. (2021) [
6] observed the greatest loss of the BCS up to the peak of production. However, in Simmental and Simmental crossbreds, body condition relative to the BCS before calving was reduced by 12–18%, while in Holsteins, it fell by 20–24%. The stronger body condition of Simmental cows was explained by research of Yan et al. (2006) [
21] and Ledinek et al. (2018) [
22], in which nutrients were more evenly distributed between the lactogenesis and restoration of the BCS in cows with lower production potential. In the present study, we observed a similar relationship between NEB markers and daily yield in both breeds. The observed trends were confirmed by their significant correlations with DMP and the length of lactation. Knob et al. (2021) [
6] found that the genetic group influenced yield at the peak of lactation and the time when the peak was attained. In comparison with Holstein cows, the production potential of the Simmental breed was much lower, as these authors noted a reduction in daily yield by about the fourth week of lactation. In our study, the reduction in DMP occurred much later. This difference could be explained by the much lower milk yield of the breeds analysed in our research and the study by Knob et al. (2021) [
6]. Our study also showed a greater production potential in HF cows. SIM cows, on the other hand, had a greater capacity to correct the NEB, and after the peak of lactation, their BCS was more quickly restored. In this respect, the results of our study were consistent with those reported by Knob et al. (2021) [
6]. Furthermore, Knob et al. (2021) [
6] showed that the interaction of breed and the stage of lactation only affects NEB markers (NEFA and BHBA) to a certain extent. In contrast with our results, Knob et al. [
6] found that these differences began to vanish from the fourth week of lactation. A study by Ingvartsen and Andersen (2000) [
23] showed that due to genetic determinants, feed consumption in early lactation has a minor influence on milk production. Yan et al. (2006) [
21], however, found that diet quality remains a significant factor by maintaining body condition during lactation and allowing cows to meet their genetic potential. According to Friggens et al. (2007) [
24], changes in milk production during lactation are mainly determined by hormone metabolism, which determines the distribution of energy resources released from fat stores. In a study by Ledinek et al. (2018) [
22], differences in the yield between breeds began to vanish in late lactation. Like Friggens et al. (2007) [
24], they observed a decrease in hormones involved in milk secretion. Ledinek et al. (2018) [
22] and Friggens et al. (2007) [
24] observed a decrease in NEFA and an increase in glucose content as lactation progressed. In light of research by Ledinek et al. [
22], Yan et al. (2006) [
21], and Friggens et al. (2007) [
24], the effects of breed and lactation on the content of the anorectic hormone leptin noted in our study are not without significance. Ledinek et al. (2018) [
22] noted a higher BCS and a faster restoration of body condition to the state immediately after calving in cows of the Fleckvieh breed in comparison to HF. The differences in leptin content noted between breeds in our study and its positive correlation with the LBCS indicated that its anorectic function may delay the restoration of the BCS. According to Ledinek et al. (2018) [
22] and Yan et al. (2006) [
21], genetic potential is not without influence on changes in the BCS. In a study by Stengarde et al. (2008) [
25], the trends in glucose content were similar to those noted in our study, and its level depended, in part, on the intensity of lactogenesis. Our study also showed that lower glucose content is accompanied by a greater loss of the BCS and a higher NEFA content. These results were in contrast to those reported by Knob et al. [
6]. Though they found the highest glucose content in Simmental cows, there was no significant difference in comparison with the Holstein breed. The function of the NEB and dry matter intake were also affected by the level of glucose present in the body. Glucose content is generally lower during periods of limited feed intake and at high concentrations of NEFA [
20]. Šamanc et al. (2015) [
26] showed that glucose concentration was usually lower in cows with a greater loss of the BCS. In their research, the glucose content in these cows was 0.16–0.72 mmol L
−l lower and NEFA content was 0.12–0.20 mmol L
−1 higher. This could be explained by the reduced glucogenic efficiency of liver cells, especially in cows with a greater reduction in the BCS and with a higher rate of BHBA production [
27]. This is in agreement with research by Loor et al. (2007) [
28], in which induced ketosis led to a marked decrease in glucose content and a sudden increase in NEFA. Drackley et al. (2001) [
3], however, did not find glucose concentration to be dependent on NEB. In that study, the glucose levels in groups of cows differing in NEFA (as an indicator of NEB) content were similar, and no relationship was shown between the contents of glucose and insulin. The correlation coefficients obtained in our study indicated that the glucose level in the blood was negatively correlated with leptin. It was also strongly positively correlated with the BCS and strongly negatively correlated with DMP and markers of NEB. Cows with a greater NEB—especially in terms of BCS loss and increased levels of C16:0, C18:0, and C18:1—had lower glucose levels. The higher levels of these FAs may be explained by research by Stoop et al. (2009) [
29], in which cows with NEB had increased contents of C16:0 and C18:0. According to the authors, this may indicate an increased mobilization of body fat reserves to provide substrates for the de novo synthesis of FA. Our study also showed that NEB can cause changes in the content of certain FA fractions, and the magnitude of these changes may be associated with both the lactation stage and breed. Research by Weber et al. (2013) [
20] and Bastin et al. (2011) [
30] also showed an increase in the proportion of LCFA, mainly up to the peak of lactation. After this time, they observed a stronger increase in the content of SFAs, including C18:0. In our study, we noted a slight decrease in this fraction as lactation progressed. However, we found that the stage of lactation affected the share of UFAs and that it was higher in the milk of Simmental cows than in the milk of HF. Roche et al. (2009) [
31] and Ducháček et al. (2020) [
19] demonstrated that the milk of cows with a mild NEB and a less severe loss of the BCS had a lower content of SFA. This may explain the results of our study, in which SFA content was lower following the period of intensive milk production and the reduction in the NEB. The differences we noted between breeds may, to some extent, be explained by research by Bastin et al. (2011) [
30] that showed that changes in the structure of milk fat may be influenced by individual traits and genetic potential. The effect of the rate of production, resulting from the genetic potential of the breed, on the FA profile was also confirmed by Samková et al. (2014) [
32] and Młynek et al. (2021) [
33]. On the other hand, studies by Kay et al. (2005) [
27] found that selection for milk yield was not the main factor determining the FA profile of milk. Petit and Côrtes (2010) [
34] reported a positive correlation between SFA and an increase in the level of BHBA produced in the liver, but they noted these changes in cows fed ground flax seeds. This diet caused an increase in the share of MUFAs and PUFAs in the milk. In our study, in which both breeds received a similar diet, Simmental cows produced milk with a more favourable FA profile and also had lower BHBA and NEB markers. Furthermore, the milk of Simmental cows usually contained less urea (MUN), another product of metabolic changes in the liver [
35]. However, this situation may have been influenced by the greater intake of biodegradable nitrogen, as the HF cows, due to their greater production, may have ingested more concentrate feed to compensate for their greater milk yield. MUN content is determined by numerous factors [
36,
37]. Studies by Kohn et al. (2002) [
38] and Spek (2013) [
39] indicated that a large portion of it arises from protein supplied with the diet. Following the detoxification of ammonia in the liver, it can then be eliminated, in part with the milk [
40]. Of course, maintaining a balance between the intake of protein and energy in the diet plays a major role [
41]. Our study, however, indicated that NEB also has a significant effect, as we observed higher MUN values in cows with faster BCS losses and higher contents of NEB markers, which were metabolized, in part, in the liver. The NEB’s function is also associated with the level of glucose present in the body. Glucose content is generally lower during periods of limited feed intake and at high concentrations of NEFA [
20]. Šamanc et al. (2015) [
26] showed that the glucose concentration was usually lower in cows with a greater loss of the BCS. In these cows, glucose content was 0.16–0.72 mmol L lower and the NEFA content was 0.12–0.20 mmol L higher. This can be explained by the reduced glucogenic efficiency of liver cells, especially in cows with a greater reduction in the BCS and a higher rate of BHBA production [
40]. This is in agreement with research by Loor et al. (2007) [
28], in which induced ketosis led to a marked decrease in glucose content and a sudden increase in NEFA. Drackley et al. (2001) [
3], however, did not find glucose concentration to be dependent on NEB. In that study, the glucose level in groups of cows differing in NEFA content was similar, and no relationship was shown between the contents of glucose and insulin. In contrast with our study, Blum et al. (1983) [
42] showed no differences in blood glucose levels between genetic groups, including HF and Simental. In their opinion, variation in glucose content is mainly influenced by the stage of lactation. However, a study by Djokovic et al. (2011) [
43] indicated that it also depends on daily milk production. This may explain the differences obtained in our study between the HF and Simmental breeds, which had different intensities of lactogenesis in the first stage of lactation. In our study, higher glucose levels were usually noted in cows with smaller losses of the BCS and lower levels of NEFA and BHBA. At the same time, leptin content was lower in these cows, which may indicate a link with stronger appetite [
5].