Obesity promotes lipid accumulation in mouse cartilage-A potential role of acetyl-CoA carboxylase (ACC) mediated chondrocyte de novo lipogenesis.

Obesity promotes the development of osteoarthritis (OA). It is also well-established that obesity leads to excessive lipid deposition in nonadipose tissues, which often induces lipotoxicity. The objective of this study was to investigate changes in the levels of various lipids in mouse cartilage in the context of obesity and determine if chondrocyte de novo lipogenesis is altered. We used Oil Red O to determine the accumulation of lipid droplets in cartilage from mice fed high-fat diet (HFD) or low-fat diet (LFD). We further used mass spectrometry-based lipidomic analyses to quantify levels of different lipid species. Expression of genes involving in fatty acid (FA) uptake, synthesis, elongation, and desaturation were examined using quantitative polymerase chain reaction. To further study the potential mechanisms, we cultured primary mouse chondrocytes under high-glucose and high-insulin conditions to mimic the local microenvironment associated with obesity and subsequently examined the abundance of cellular lipid droplets. The acetyl-CoA carboxylase (ACC) inhibitor, ND-630, was added to the culture medium to examine the effect of inhibiting de novo lipogenesis on lipid accumulation in chondrocytes. When compared to the mice receiving LFD, the HFD group displayed more chondrocytes with visible intracellular lipid droplets. Significantly higher amounts of total FAs were also detected in the HFD group. Five out of six significantly upregulated FAs were ω-6 FAs, while the two significantly downregulated FAs were ω-3 FAs. Consequently, the HFD group displayed a significantly higher ω-6/ω-3 FA ratio. Ether linked phosphatidylcholine was also found to be higher in the HFD group. Fatty acid desaturase (Fad1-3), fatty acid-binding protein 4 (Fabp4), and fatty acid synthase (Fasn) transcripts were not found to be different between the treatment groups and fatty acid elongase (Elovl1-7) transcripts were undetectable in cartilage. Ceramide synthase 2 (Cers-2), the only transcript found to be changed in these studies, was significantly upregulated in the HFD group. In vitro, chondrocytes upregulated de novo lipogenesis when cultured under high-glucose, high-insulin conditions, and this observation was associated with the activation of ACC, which was attenuated by the addition of ND-630. This study provides the first evidence that lipid deposition is increased in cartilage with obesity and that this is associated with the upregulation of ACC-mediated de novo lipogenesis. This was supported by our observation that ACC inhibition ameliorated lipid accumulation in chondrocytes, thereby suggesting that ACC could potentially be targeted to treat obesity-associated OA.

Health benefits attributed to 17α-estradiol, a lifespan-extending compound, are mediated through estrogen receptor α.

Metabolic dysfunction underlies several chronic diseases, many of which are exacerbated by obesity. Dietary interventions can reverse metabolic declines and slow aging, although compliance issues remain paramount. 17α-estradiol treatment improves metabolic parameters and slows aging in male mice. The mechanisms by which 17α-estradiol elicits these benefits remain unresolved. Herein, we show that 17α-estradiol elicits similar genomic binding and transcriptional activation through estrogen receptor α (ERα) to that of 17ß-estradiol. In addition, we show that the ablation of ERα completely attenuates the beneficial metabolic effects of 17α-E2 in male mice. Our findings suggest that 17α-E2 may act through the liver and hypothalamus to improve metabolic parameters in male mice. Lastly, we also determined that 17α-E2 improves metabolic parameters in male rats, thereby proving that the beneficial effects of 17α-E2 are not limited to mice. Collectively, these studies suggest ERα may be a drug target for mitigating chronic diseases in male mammals.

17α-estradiol acts through hypothalamic pro-opiomelanocortin expressing neurons to reduce feeding behavior.

Weight loss is an effective intervention for diminishing disease burden in obese older adults. Pharmacological interventions that reduce food intake and thereby promote weight loss may offer effective strategies to reduce age-related disease. We previously reported that 17α-estradiol (17α-E2) administration elicits beneficial effects on metabolism and inflammation in old male mice. These observations were associated with reduced calorie intake. Here, we demonstrate that 17α-E2 acts through pro-opiomelanocortin (Pomc) expression in the arcuate nucleus (ARC) to reduce food intake and body mass in mouse models of obesity. These results confirm that 17α-E2 modulates appetite through selective interactions within hypothalamic anorexigenic pathways. Interestingly, some peripheral markers of metabolic homeostasis were also improved in animals with near complete loss of ARC Pomc transcription. This suggests that 17α-E2 might have central and peripheral actions that can beneficially affect metabolism cooperatively or independently.

Time-dependent effects of safflower oil to improve glycemia, inflammation and blood lipids in obese, post-menopausal women with type 2 diabetes: a randomized, double-masked, crossover study.

BACKGROUND & AIMS: Metabolic effects of dietary fat quality in people with type 2 diabetes are not well-understood. The study objective was to evaluate effects of conjugated linoleic acid (CLA) and safflower (SAF) oils on glycemia, blood lipids, and inflammation. The hypothesis we tested is that dietary oils improve glycemia, lipids, and inflammatory markers in a time-dependent way that follows accumulation of linoleic acid and CLA isomers in serum of subjects supplemented with dietary oils. METHODS: Fifty-five post-menopausal, obese women with type 2 diabetes enrolled, and 35 completed this randomized, double-masked crossover study. Treatments were 8 g daily of CLA and SAF for 16 weeks each. We used a multiple testing procedure with pre-determined steps analysis to determine the earliest time that a significant effect was detected. RESULTS: CLA did not alter measured metabolic parameters. SAF decreased HbA1c (-0.64 ± 0.18%, p = 0.0007) and C-reactive protein (-13.6 ± 8.2 mg/L, p = 0.0472), increased QUICKI (0.0077 ± 0.0035, p = 0.0146) with a minimum time to effect observed 16 weeks after treatment. SAF increased HDL cholesterol (0.12 ± 0.05 mmol/L, p = 0.0228) with the minimum time to detect an effect of SAF at 12 weeks. The minimum time to detect an increase of c9t11-CLA, t10c12-CLA, and linoleic acid in serum of women supplemented CLA or SAF, respectively, was four weeks. CONCLUSIONS: We conclude that 8 g of SAF daily improved glycemia, inflammation, and blood lipids, indicating that small changes in dietary fat quality may augment diabetes treatments to improve risk factors for diabetes-related complications.

c9t11-Conjugated linoleic acid-rich oil fails to attenuate wasting in colon-26 tumor-induced late-stage cancer cachexia in male CD2F1 mice.

SCOPE: Cancer cachexia is characterized by muscle and adipose tissue wasting caused partly by chronic, systemic inflammation. Conjugated linoleic acids (CLAs) are a group of fatty acids with various properties including anti-inflammatory cis9, trans11 (c9t11)-CLA and lipid-mobilizing trans10, cis12 (t10c12)-CLA. The purpose of this study was to test whether dietary supplementation of a c9t11-CLA-rich oil (6:1 c9t11:t10c12) could attenuate wasting of muscle and adipose tissue in colon-26 adenocarcinoma-induced cachexia in mice. METHODS AND RESULTS: Loss of body weight, muscle and adipose tissue mass caused by tumors were not rescued by supplementation with the c9t11-CLA-rich oil. In quadriceps muscle, c9t11-CLA-rich oil exacerbated tumor-induced gene expression of inflammatory markers tumor necrosis factor-α, IL-6 receptor and the E3 ligase MuRF-1 involved in muscle proteolysis. In epididymal adipose tissue, tumor-driven delipidation and atrophy was aggravated by the c9,t11-CLA-rich oil, demonstrated by further reduced adipocyte size and lower adiponectin expression. However, expression of inflammatory cytokines and macrophage markers were not altered by tumors, or CLA supplementation. CONCLUSION: These data suggest that addition of c9t11-CLA-rich oil (0.6% c9t11, 0.1% t10c12) in diet did not ameliorate wasting in mice with cancer cachexia. Instead, it increased expression of inflammatory markers in the muscle and increased adipose delipidation.

Postnatal hepatic fatty acid oxidative capacity of preterm pigs receiving TPN does not differ from that of term pigs and is not affected by supplemental arachidonic and docosahexaenoic acids.

To improve pediatric care of preterm infants, a better understanding of the metabolic processes associated with immaturity is needed. To this end, preterm and term pigs were delivered and administered either a control, a low-PUFA [0.3 and 0.6% of total lipids as docosahexaenoic acid (DHA) and arachidonic acid (AA), respectively], or a high-PUFA (5 and 11% of total lipids as DHA and AA, respectively) parenteral solution. Hepatic oxidative capacity and carnitine palmitoyltransferase (CPT) mRNA and activity in the presence or absence of malonyl-CoA were determined after 6 d. Oxidation of [1-(14)C]-palmitate or [1-(14)C]-glucose was similar in liver homogenates isolated from preterm and term pigs receiving the control solution. Oxidative capacity for either substrate did not differ with parenteral solution in preterm pigs, whereas in term pigs, glucose oxidation was 64% greater when the high-PUFA solution was administered relative to the control (P < 0.05). In preterm pigs, CPT I mRNA determined after 6 d of parenteral feeding were 1.5-fold greater (P < 0.05) than newborn estimates irrespective of solution administered, whereas CPT I mRNA were only greater for term pigs receiving the low- and high-PUFA solutions (66 and 115%, respectively; P < 0.05) relative to newborn estimates. Malonyl-CoA-sensitive CPT activity did not differ between preterm and term pigs or parenteral solution. Postnatal adaptations demonstrated by parenterally fed term neonates are present following preterm birth and are not improved by the provision of DHA and AA to parenteral solutions.