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Energy homeostasis is subjected to a circadian control that synchronizes energy intake and expenditure. The transcription factor CLOCK, a key component of the molecular circadian clock, controls many kinds of rhythms, such as those for locomotor activity, body temperature, and metabolic functions. The purpose of the present study is to understand the function of the Clock gene during lipid metabolism in the liver using Clock-mutant mice. Clock-mutant mice with an ICR background were fed a high-fat diet for 13 weeks, and liver triglyceride, serum triglyceride, and serum free fatty acid levels were examined. Triglyceride content in the liver was significantly less increased in Clock-mutant mice on a high-fat diet compared to wild-type mice on a high-fat diet. Acsl4 and Fabp1 mRNA levels in the liver showed daily rhythms in wild-type mice. In contrast, Clock -mutant mice had attenuated daily rhythms of Acsl4 and Fabp1 gene expression in the liver under both normal and high-fat diet conditions compared to wild-type mice. In Clock-mutant mice, suppression of Acsl4 and Fabp1 mRNA in the liver under high-fat diet conditions may have attenuated the accumulation of triglycerides in the liver compared to wild-type mice under the same conditions. In conclusion, the authors demonstrate that mice with a Clock mutation showed less triglyceride accumulation in the liver through the suppression of Acsl4 and Fabp1 gene expression when fed a high-fat diet compared to wild-type mice fed the same diet.

Adequate folate status in pregnancy is important for satisfactory pregnancy outcome.The objective of the present study was to evaluate folate status in healthy pregnant women by assessing dietary folate intakes and measuring changes in folate-related biomarkers including plasma tHcy, serum vitamin B(12) (B(12)), and serum and RBC folate concentrations in each trimester and to examine their relation to fetal growth.From 94 pregnant women, 3-day-dietary records were obtained and blood was collected for plasma total homocysteine (tHcy), serum B(12), and serum and red-blood cell (RBC) folate measurements. Infant anthropometric measurements were made immediately after birth.Average folate intake was less than 300 microg/day with a mean energy intake of about 1800 kcal. Mean serum and RBC folate concentrations declined significantly during gestation (p0.05). Mean serum B(12) also significantly decreased (p0.01), whereas plasma tHcy increased from 5.1 in the first trimester to 5.9 micromol/l in the third trimester (p0.01). Multiple regression analyses, after controlling for maternal age, parity and pre-pregnancy body-mass index indicated that a 1.0 micromol/l increase in plasma tHcy in the third trimester corresponded to a 151 g decrease in birth weight (p0.01). Neither B(12) nor folate concentrations in all three trimesters showed any significant associations with birthweight. Plasma pyridoxal-5'-phosphate concentrations were markedly low, and were consistent with low intake of vitamin B(6) in our population.Our data suggest that higher plasma tHcy in the third trimester is a predictor of lower birth weight. In general, the dietary intake of B-vitamins and energy may be inadequate in our population, suggesting intervention is necessary.

Objective: It is known that immune functions are altered in various ways by obesity. However, changes in the intestinal immune system resulting from obesity remain poorly understood. Oral tolerance is a system that suppresses antigen specific immune responses to orally administrated antigens. The intestinal immune system is intimately associated with the oral tolerance system, that acts to prevent allergic and inflammatory diseases. In this study we investigated the effect of obesity on induction of oral tolerance to ovalbumin (OVA) in an animal model of obesity. Research methods and procedures: Obese mice induced by a high fat diet and control mice were allowed free access for 3 days to a 1%-ovalbumin (OVA) solution in drinking water. After continuous feeding of the antigen, all the mice were immunized by two intraperitoneal injections of OVA administered 7 days apart. Results: In the control mice, induction of oral tolerance caused an increase in antigen specific IgG1 levels and a decrease in IgG2a levels. In contrast, the IgG1/IgG2a ratio was reversed in obese mice. OVA-specific IL-2 production was suppressed by antigen feeding in both the control and obese mice; however, suppression of OVA-specific IL-10 was observed only in the control mice. Although OVA-specific IgA and IgM were not affected by antigen feeding, the obese groups of mice had significantly lower titers of antibodies. Discussion: These findings suggest that obesity may affect induction of oral tolerance following antigen feeding and that these changes may be related to the inflammatory reaction.

日本人のn-3系多価不飽和脂肪酸 (以下n-3系脂肪酸と略す) の摂取基準策定 (2005年版) に用いた論文をエビデンステーブル (表) として提示し, 策定の基本的な考え方を詳しく述べた。n-3系脂肪酸は一定量以下のある摂取量で皮膚炎, 成長障害が認められる必須脂肪酸であるので, 下限の設定 (最低必要量) が必要である。しかし, 報告症例が少なく, 一定量以下のある摂取量を求めることができないため, 摂取量の中央値で表される目安量を用いた。すなわち, 大部分の日本人では皮膚炎は認められていないので, 日本人の各年齢階層における男女別にみたn-3系脂肪酸摂取量の中央値を日本人の大多数で欠乏症状が認められない十分な量と考え, 目安量とした。このように安全幅が広めに設定されているため, 実際の摂取量が目安量より少なくても欠乏症状はあらわれないと思われる。n-3系脂肪酸を多く摂取すると, 虚血性心疾患罹患が少なくなることを示す欧米の報告は多い。しかし, 現在の日本人のn-3系脂肪酸摂取量の中央値は, 欧米人の検討成績の中で, 虚血性心疾患罹患率の最も低い, 最高分位のn-3系脂肪酸摂取量のグループの中央値よりも多い。このため, 日本人のn-3系脂肪酸摂取量の中央値程度を摂取していれば, 虚血性心疾患罹患率を十分低くできると考えられる。そこで, 18歳以上に対し, n-3系脂肪酸摂取量の中央値を, 目標量 (生活習慣病予防を目的とした食事摂取基準の一つ) の下限と設定した。設定された18歳以上の目標量は2.0-2.9g/day以上となる。この値は必須脂肪酸としての目安量と一致するため, 18歳以上については目標量のみの設定となっている。n-3系脂肪酸を多く摂取した場合の弊害についても検討した。出血時間の延長, LDL-コレステロール値の増加が多く報告されているが, 臨床的に問題となる出血例の増加は報告されていないし, 虚血性心疾患罹患率が増加したことを示す報告もない。このため, 今回の策定では, 目標量の上限値設定は行わなかった。しかしながら, 日本人のおもなn-3系脂肪酸摂取源である魚介類には, 水銀, カドニウムなどの重金属, ダイオキシン, PCBなどの環境汚染物質が微量ながら含まれる。食事摂取基準では, 有害物質の摂取量について取り扱っていないため, これらの影響については考慮されていない。この点を補完するために, 本稿では水銀摂取の影響についてエビデンスの収集を行い, 妊婦が魚を摂取する場合の注意点についても言及した。

食餌誘導性肥満モデルマウスを用いて拘束ストレス負荷による免疫能の変化を検討した。4週齢C57BL/6J系雌マウスを普通食 (control 群) および高脂肪食 (obese 群) にて9週間飼育し, その間に12時間の拘束ストレス負荷 (stress (+) 群), または絶食のみ (stress (-) 群) の直後, 計2回卵白アルブミン (OVA) を腹腔内免疫した。血中レプチン値は obese 群で高値を示し, 拘束ストレス負荷によってさらに有意に増加した。両群ともにストレス負荷により脾臓1gあたりのリンパ球数が減少しリンパ球増殖反応も低下した。抗原刺激によるIL-2およびIL-4はともにストレス負荷により増加したが, 抗原特異的抗体価は高脂肪食により低下しストレスを負荷した obese 群で最も低い値を示した。ストレス負荷により抗原特異的な免疫反応に変化が生じ, さらにストレス負荷時の obese 群の免疫機能にはレプチンが影響を与える可能性がある。

日本人の食事摂取基準 (2005年版) のコレステロールに関する基本的考え方を解説した。至適コレステロール摂取量は, 疾病の罹患率, 死亡率が低くなるように, 今までの大規模観察研究や介入研究の報告を基に, 日本人のコレステロール摂取量を考慮して設定されるべきである。食事性コレステロール摂取量は血中コレステロール値に一般的には大きな影響を与えないが, 個人差があり, 欧米人に比べ, 肥満が少なく, 飽和脂肪酸摂取量の少ない日本人では, 食事性コレステロールによる血中コレステロール値の影響が欧米人に比べ, 大きい可能性がある。日本人も欧米人と同様, 血中総コレステロール値が高くても, 低くても死亡率は増加する。血中総コレステロール高値による死亡率増加はLDL-コレステロール値増加によって生じる動脈硬化が主因と考えられるが, 血中総コレステロール低値による死亡率増加は, 基盤にある消耗性疾患 (がん, 呼吸器疾患, 貧血, 感染症等) が原因と考えられる。観察研究では, 食事性コレステロール摂取量と総死亡率, 虚血性心疾患発症率, 脳卒中発症率との関連は認められていない。しかし, 日本人高齢者の糖尿病罹患率はこの5年間で増加しているため, 今後血中コレステロール値が増加すると, 糖尿病等の動脈硬化性疾患の危険因子をもった人では, 動脈硬化性疾患が増加する可能性が高い。また, 食事性コレステロール摂取量は肺がん, 消化器がん (膵臓がんや大腸/直腸がん) と正の関連を示す報告がある。以上の結果から, 多量のコレステロール摂取は好ましくなく, 成人ではコンステロール摂取量の上限値設定が必要と考えられた。

Some epidemiologic surveys have demonstrated that asthma is more prevalent in obese children and adults. However, the mechanism of association between obesity and asthma has not been fully clarified. This report investigates a murine model for antigen-induced asthma and diet-induced obesity from an immunologic perspective. For the induction of obesity, C57BL/6J mice were fed a high-fat diet supplemented with lard or soybean oil. Mice were then sensitized and challenged with ovalbumin (OVA) to induce allergic lung inflammation. OVA-specific serum immunoglobulin levels were lower in obese mice compared with non-obese control mice. The decline of OVA-specific IgE in the soybean oil group was found to be especially pronounced. However, obese mice with OVA-induced asthma showed a higher sensitivity of antigen-induced T-cell responses, and increased gamma interferon (IFN-gamma) production of splenocytes with phytohemagglutinin (PHA) stimulation. Furthermore, mast cell numbers in the tracheal mucosa were increased in obese mice upon sensitization by OVA. These results suggest that obesity-induced changes in T-cell function may be partly involved in the pathophysiology of asthma in human obesity, rather than Ig E-mediated allergic responses.

Although decreased T-cell function has been observed in obese human subjects and genetically obese animals, the precise role of immune functions in obesity is still unclear. To investigate immune functions in obesity, we examined the proliferative responses of splenic lymphocytes and their capacity to produce cytokines in the presence or absence of leptin, the protein produced by the obese gene, in diet-induced obese and control mice. For induction of obesity, C57BL/6J mice were fed a high-fat diet for 13 weeks. In mice fed the high-fat diet, body weight, fat pad weight, and tumor necrosis factor (TNF) alpha production by adipocytes were significantly increased relative to mice fed the normal diet. Lipopolysaccharide (LPS) stimulated proliferation of cultured splenocytes from diet-induced obese mice was also increased. However, production of interleukin (IL)-2 by splenic lymphocytes from obese mice was suppressed, whereas interferon (IFN)-gamma and IL-4 production was increased. Exogenous lepitn regulated the cytokine production by cultured splenocytes from control and obese mice, respectively (upregulation of IFN-gamma and downregulation of IL-2 in control mice, and downregulation of IL-4 in obese mice). These results suggest that changes in cytokine production by splenic lymphocytes in obesity are indicative of altered immune functions that might contribute to related complications, although the effect of difference in nutrient intake (macro and micro) may also have contributed to the changes.

Objective Protein-energy malnutrition (PEM) is a serious nutritional problem that causes immune dysfunction in elderly people. Probiotic lactic acid bacteria may potentially modify immunity; however, there is little evidence to elucidate the influence of these bacteria on PEM in the elderly. Methods The immune modulation effects of lactic acid bacterium Lactobacillus johnsonii La1 (La1) were examined in aged mice and aged mice with PEM. Twenty-month-old male 57BL6/n mice ( n = 28) were divided into four groups and received the following diet for 14 d: a complete diet (20% protein) without Lal (control) or with Lal or a low-protein diet (5% protein) to induce PEM, with or without La1. All mice were immunized with diphtheria toxin (DT) with alfacalciferol at 7 d and sacrificed 14 d after starting the experimental diets. Results Serum albumin concentrations and body weight, both of which were reduced by the low-protein diet, were ameliorated by La1 intake and were the same as in mice receiving the control diet. Anti-DT immunoglobulin (Ig) A in fecal extract was increased by La1 intake in mice receiving the complete and low-protein diets. Serum anti-DT IgA, IgG, splenocyte proliferation, and CD8 + T cells were reduced by the low-protein diet and restored by La1 intake. Conclusion La1 enhances intestinal IgA production and helps recover nutritional status and systemic immune responses in aged mice with PEM. It is possible that La1 may contribute to immune system recovery in immunocompromised hosts such as elderly humans with PEM.

Leptin can regulate several immune functions. However, the role of leptin on lymphocyte function has not been recognized in vivo. Accordingly, we have investigated the effect of leptin on starvation-induced immune dysfunction using diet-induced obese mice. To induce obesity, C57BL/6J mice were fed a high-fat diet for 14 weeks and control mice were fed a standard diet for the same period. The obese and control groups of mice were then starved for 48 h, and received intraperitoneal injections of recombinant leptin or phosphate-buffered saline four times during starvation. Other control mice in both diet groups were free fed without being starved. Although starvation of the control mice dramatically reduced the weights of the immune organs, cytokine production and increased proliferation of cultured splenocytes, these levels returned to those of the free-feeding groups with exogenous leptin administration. However, these effects of leptin were not observed in obese mice. These findings provide some evidence that leptin can regulate the immune function in vivo. It is also suggested that the action of leptin might not appear in obesity.

Background: Estrogen plays an important modulatory role in the immune system, and is concerned with the pathophysiology of autoimmune diseases such as rheumatoid arthritis (RA), although the mechanism has not yet been clarified. Oral tolerance, a form of specific peripheral tolerance, which is recognized as a new therapeutic strategy, is related to the function of gut-associated lymphoid tissue. Methods: In this study, using collagen-induced arthritis as an animal model of RA, the effects of 17β-estradiol (E2) on oral tolerance induction were investigated. For induction of oral tolerance, mice were fed 60 µg type II collagen (CII) for 10 consecutive days prior to each CII immunization. Mice in the E2 treatment groups were injected with 5 µg (low dose) or 500 µg (high dose) E2 three times during the induction of oral tolerance. Results: Oral tolerance induction suppressed the occurrence of arthritis, the proliferative response of splenocytes to CII and the specific DTH response. However, E2 treatment abrogated the suppression, which might be connected with a change in function of Peyer’s patch (PP) lymphocytes. Conclusion: These results suggest that oral tolerance induction might be affected by estrogen treatment through alteration of intestinal immune responses.

Objective To understand the effect of obesity and insulin on immune functions in non-insulin-dependent diabetes mellitus (NIDDM). Subject Fourteen obese NIDDM (body mass index (BMI)=30.6+/-1.1), seven non-obese NIDDM (BMI=24.2+/-0.5) and five obese non-NIDDM (BMI=28.3+/-0.67). Interventions We first examined the influence of insulin on the proliferation of several human cell lines. Second, we compared several immune functions between obese and non-obese NIDDM, and obese non-NIDDM patients using peripheral blood mononuclear cells. Result Insulin decreased proliferation of T-cell lines but not that of other types of cell lines. Furthermore, obesity augmented the production of IL-1beta which could have cytotoxity against islet beta cells in NIDDM. Conclusion Our data suggested that the pathophysiology of NIDDM could be affected by the change of immunity due to obesity, and the treatment of obesity in NIDDM may be important from an immunological aspect.