GLP-1-mediated delivery of the PPAR𝛼/𝛾 dual-agonist Tesaglitazar improves obesity and glucose metabolism in mice

Dual-agonists activating the peroxisome proliferator-activated receptors alpha and gamma (PPAR𝛼/𝛾) have shown beneficial effects on glucose and lipid metabolism in patients with type 2 diabetes, but their development was discontinued due to unfavorable cardiovascular and/or renal effects. Here we report the design and preclinical evaluation of a molecule that covalently links the PPAR𝛼/𝛾 dual-agonist Tesaglitazar to GLP-1 to allow for the GLP-1 receptor-dependent delivery of Tesaglitazar. GLP-1/Tesaglitazar does not differ from matched GLP-1 in GLP-1R signaling, but shows GLP-1R-dependent PPAR𝛾-RXR heterodimerization with enhanced efficacy to improve body weight, food intake, and glucose metabolism relative to GLP-1 or Tesaglitazar in mice with diet- and genetically-induced obesity. The conjugate fails to affect body weight and glucose metabolism in GLP-1R knockout (ko) mice and shows preserved effects in DIO mice at doses subthreshold for GLP-1 and Tesaglitazar to improve metabolism. Consistent with the GLP-1R expression pattern, LC/MS-based proteomics identified a series of novel PPAR protein targets in the hypothalamus that are acutely upregulated by Tesaglitazar and by GLP-1/Tesaglitazar, but not by treatment with GLP-1. Collectively, our data show that GLP-1/Tesaglitazar improves energy and glucose metabolism with superior efficacy to GLP-1 or Tesaglitazar alone and suggest that this conjugate holds therapeutic value to treat hyperglycemia and insulin resistance.

Prevalence and Associated Factors of Malnutrition in Patients with Intracranial Infections at Sanglah Hospital Denpasar

Malnutrition is a major health problem in developing countries, it can occur acutely, chronically or combination of both. Malnutrition aggravates the condition of infectious diseases, including intracranial infections. Hereby we aimed to determine the prevalence and factors associated with malnutrition in pediatric patients with intracranial infections in Sanglah Central General Hospital. This cross-sectional analytic study was conducted in patients with final diagnosis intracranial infection whom were treated from January 2019 to March 2021. The study was conducted in pediatric patients aged 1 month-18 years old and patient would be excluded if had any of these conditions: 1) incomplete medical records, 2) discharge by his/her own request, 3) hydrocephalus for which VP shunt had not been performed, 4) diagnosis of tumor or mass that could affect body weight measurement. Secondary data such as weight/height for children <5 years and BMI/age for children >5 years were measured in growth curve by using the WHO Anthro application. Total samples were 83 children with predominance age group was 0-5 years old. Malnutrition was found in 48.1% patients. Chronic malnutrition was more common than acute malnutrition (32.5% vs. 31.3%). Age below 5 years has relationship with the incidence of acute malnutrition in pediatric patients with intracranial infection (p: 0.008, 95% CI: 0.076-0.675). The incidence of malnutrition in children with intracranial infections in Sanglah Hospital during January 2019 to March 2021 was 48.1%, and age < 5 years had significant relation to the incidence of malnutrition in children with intracranial infections.

Substitusi rumput lapang dengan hay African Star Grass (Cynodon plectostachyus) terhadap produktivitas kelinci lokal jantan

The purpose of this research was to determine field grass substitution by hay African Star Grass (Cynodon plectostachyus) on the productivity of local male rabbits with an age of 3 months old. The research was conducted in October-November 2020 in Central Pojok Village, Cikahuripan, Lembang, West Bandung Regency. The research method used a completely randomized design with five treatments which were P0: 80% field grass + 20% concentrate; P1: 60% field grass + 20% hay African Star Grass + 20% concentrate; P2: 40% field grass + 40% hay African Star Grass + 20% concentrate; P3: 20% field grass + 60% hay African Star Grass + 20% concentrate; P4: 80% African Star Grass hay + 20% concentrate, and each treatment was repeated five times so that the number of rabbits used were 25 heads. Data obtained were analyzed using SPSS software and Duncan's multiple range test. The results showed that the substitution of field grass by Afrikan Star Grass affected ration consumption (P<0.05) with an average of 150.79-185.78 grams/head/day, but did not affect body weight gain and feed conversion (P>0.05) with an average of 14.64-19.78 grams/head/day and 7.94-11.60, respectively. This study concluded that the provision of hay African Star Grass at the level of 20% showed more optimal results.

Hybrid rye may replace up to 75% of the corn in diets for gestating and lactating sows without negatively impacting sow and piglet performance

An experiment was conducted to test the hypothesis that hybrid rye can replace a part of the corn in gestation and lactation diets without negatively affecting sow and litter performance. For each phase, a corn-soybean meal diet and 3 diets in which hybrid rye replaced 25, 50, or 75% of corn were formulated. Two hundred sows were randomly allotted by parity to the 4 treatments. Results indicated that diet did not affect body weight or average daily gain (ADG) of sows, or number of pigs born. The number of pigs weaned, litter weaning weight, and litter ADG increased and then decreased (quadratic, P &lt; 0.05) as hybrid rye in diets increased. Pig mortality and number of crushed pigs tended (quadratic, P &lt; 0.10) to be reduced as hybrid rye was added to the diet. Serum cytokines did not differ among treatments on day 105 of gestation or in pigs on the day of weaning, but interleukin (IL)-4, IL-10, and IL-18 on day 13 of lactation increased and then decreased (quadratic, P &lt; 0.05) as hybrid rye inclusion increased in diets. Milk urea N increased (linear, P &lt; 0.05) as hybrid rye was included in the diet, but no other differences in milk composition were observed. Overall, replacing 25% or 50% of corn with hybrid rye resulted in improved lactation performance, and replacing 75% of corn with hybrid rye resulted in sow and litter performance that was not different from that of sows fed control diets.

STAT3 but Not ERK2 Is a Crucial Mediator Against Diet-Induced Obesity via VMH Neurons

Leptin plays an important role in the protection against diet-induced obesity (DIO) by its actions in ventromedial hypothalamic (VMH) neurons. However, little is known about the intracellular mechanisms involved in these effects. To assess the role of the STAT3 and ERK2 signaling in neurons that express the steroidogenic factor 1 (SF1) in the VMH on energy homeostasis, we used cre-lox technology to generate male and female mice with specific disruption of STAT3 or ERK2 in SF1 neurons of the VMH. We demonstrated that the conditional knockout of STAT3 in SF1 neurons of the VMH did not affect body weight, food intake, energy expenditure and glucose homeostasis in animals on regular chow. However, when challenged with high-fat diet (HFD), loss of STAT3 in SF1 neurons caused a significant increase in body weight, food intake and energy efficiency that was more remarkable in females which also showed a decrease in energy expenditure. In contrast, deletion of ERK2 in SF1 neurons of VMH did not have any impact on energy homeostasis in both regular diet and HFD conditions. In conclusion, STAT3 but not ERK2 signaling in SF1 neurons of VMH plays a crucial role to protect against DIO in a sex-specific pattern.

STAT3 but Not ERK2 Is a Crucial Mediator Against Diet-Induced Obesity via VMH Neurons

Leptin plays an important role in the protection against diet-induced obesity (DIO) by its actions in ventromedial hypothalamic (VMH) neurons. However, little is known about the intracellular mechanisms involved in these effects. To assess the role of the STAT3 and ERK2 signaling in neurons that express the steroidogenic factor 1 (SF1) in the VMH on energy homeostasis, we used cre-lox technology to generate male and female mice with specific disruption of STAT3 or ERK2 in SF1 neurons of the VMH. We demonstrated that the conditional knockout of STAT3 in SF1 neurons of the VMH did not affect body weight, food intake, energy expenditure and glucose homeostasis in animals on regular chow. However, when challenged with high-fat diet (HFD), loss of STAT3 in SF1 neurons caused a significant increase in body weight, food intake and energy efficiency that was more remarkable in females which also showed a decrease in energy expenditure. In contrast, deletion of ERK2 in SF1 neurons of VMH did not have any impact on energy homeostasis in both regular diet and HFD conditions. In conclusion, STAT3 but not ERK2 signaling in SF1 neurons of VMH plays a crucial role to protect against DIO in a sex-specific pattern.

CB1Rs in VMH Neurons Regulate Glucose Homeostasis but not Body Weight

Cannabinoid 1 receptor (CB1R) inverse-agonists reduce body weight and improve several parameters of glucose homeostasis. However, these drugs have also been associated with deleterious side effects. CB1R expression is widespread in the brain and in peripheral tissues, but whether specific sites of expression can mediate the beneficial metabolic effects of CB1R drugs, while avoiding the untoward side effects, remains unclear. Evidence suggests inverse-agonists may act on key sites within the central nervous system to improve metabolism. The ventromedial hypothalamus (VMH) is a critical node regulating energy balance and glucose homeostasis. To determine the contributions of CB1Rs expressed in VMH neurons in regulating metabolic homeostasis, we generated mice lacking CB1Rs in the VMH. We found that deletion of CB1Rs in the VMH did not affect body weight in male and female mice fed chow or HFD. We also found that deletion of CB1Rs in the VMH did not alter weight loss responses induced by the CB1R inverse-agonists SR141716. However, we did find that CB1Rs of the VMH regulate parameters of glucose homeostasis independent of body weight in diet-induced obese male mice.

Intestinal Growth in Glucagon Receptor Knockout Mice Is Not Associated With the Formation of AOM/DSS-Induced Tumors

Treatment with exogenous GLP-2 has been shown to accelerate the growth of intestinal adenomas and adenocarcinomas in experimental models of colonic neoplasia, however, the role of endogenous GLP-2 in tumor promotion is less well known. Mice with a global deletion of the glucagon receptor (Gcgr-/-) display an increase in circulating GLP-1 and GLP-2. Due to the intestinotrophic nature of GLP-2, we hypothesized that Gcgr-/- mice would be more susceptible to colonic dysplasia in a model of inflammation-induced colonic carcinogenesis. Female Gcgr-/- mice were first characterized for GLP-2 secretion and in a subsequent study they were given a single injection with the carcinogen azoxymethane (7.5 mg/kg) and treated with dextran sodium sulfate (DSS) (3%) for six days (n=19 and 9). A cohort of animals (n=4) received a colonoscopy 12 days following DSS treatment and all animals were sacrificed after six weeks. Disruption of glucagon receptor signaling led to increased GLP-2 secretion (p&lt;0.0001) and an increased concentration of GLP-2 in the pancreas of Gcgr-/- mice, coinciding with an increase in small intestinal (p&lt;0.0001) and colonic (p&lt;0.05) weight. Increased villus height was recorded in the duodenum (p&lt;0.001) and crypt depth was increased in the duodenum and jejunum (p&lt;0.05 and p&lt;0.05). Disruption of glucagon receptor signaling did not affect body weight during AOM/DSS treatment, neither did it affect the inflammatory score assessed during colonoscopy or the number of large and small adenomas present at the end of the study period. In conclusion, despite the increased endogenous GLP-2 secretion Gcgr-/- mice were not more susceptible to AOM/DSS-induced tumors.

Dampak Pemberian Mikroenkapsulasi Minyak Ikan dalam Pakan terhadap Kolesterol Darah dan Performa pada Domba

ABSTRAK. Tujuan penelitian ini untuk mengukur seberapa besar pengaruh minyak ikan yang sudah terenkapsulasi terhadap kolesterol darah dan performa pada Domba. Penelitian telah dilakukan di Sub Unit Pelayanan Pengembangan Pembibitan Ternak Domba dan Kambing (SUPPPTDK) Bunihayu, Subang pada tanggal 20 Januari 2020 sampai 27 Maret 2020. Sebanyak 18 ekor domba Ekor Tipis jantan dengan bobot 15,99±0,98 kg dialokasikan ke dalam 3 perlakuan secara acak. Domba tersebut diberi ransum perlakuan yang disuplementasi dengan mikroenkapsulasi minyak ikan sebanyak 0% (P0), 2,5% (P1), dan 5% (P2). Data yang terkumpul dilakukan analisis ragam dan bila hasil berbeda nyata maka dilanjutkan dengan uji Duncan. Hasil menunjukkan bahwa mikroenkapsulasi minyak ikan dapat menurunkan kolesterol darah (P0,05), namun tidak berpengaruh nyata terhadap pertambahan bobot badan, konsumsi dan konversi ransum (P0,05). Penurunan kadar kolesterol terjadi pada kelompok domba dengan perlakuan mikroenkapsulasi sebanyak 2,5% (P1) dan mikroenkapsulasi 5% (P2). Kadar kolesterol darah masing-masing perlakuan berturut-turut adalah 100,70 mg/dl (P0); 96,20 mg/dl (P1); dan 78,76 mg/dl (P2). Rataan yang terbaik pada pertambahan bobot badan, konsumsi bahan kering harian, dan konversi ransum terdapat pada P2 yaitu 63,96 g/hari, 574,13 g/hari, dan 9,08. Hasil penelitian dapat disimpulkan bahwa mikroenkapsulasi minyak ikan dapat menurunkan kolesterol darah, dengan penurunan tertinggi pada pemberian 5%. (The impact of microencapsulation fish oil in feed on blood cholesterols and performance on sheep) ABSTRAK. This study measured the effect of encapsulated fish oil on blood cholesterol and sheep performance. The study was conducted at the Bunihayu Sheep and Goat Breeding Services Bunihayu, Subang on January 20, 2020 to March 27, 2020. A total of 18 male thin-tailed sheep 15.99±0.98 kg were allocated randomly into 3 treatments. The sheep were given feed supplemented with fish oil microencapsulation of 0% (P0), 2.5% (P1), and 5% (P2). The data were collected and analyzed by analysis of variance and, if the result is significantly different, continued by Duncan's test. The results showed that fish oil microencapsulation decreased blood cholesterol levels (P0.05). However, it did not affect body weight gain, consumption, and feed conversion (P0.05). Decreased levels of cholesterol occurred in the group of sheep with 2.5% microencapsulation (P1) and 5% microencapsulation (P2). Blood cholesterol levels of each treatment were 100.70 mg/dl (P0); 96.20 mg/dl (P1); and 78.76 mg/dl (P2), respectively. Averagely, the highest body weight gain, dry matter intake and feed conversion were found in P2 as much as 63.96 g/day, 574.13 g/day, and 9.08, respectively. The results can be concluded that microencapsulation of fish oil can reduce blood cholesterol, with the highest decrease at the level of 5%.