The liver is an essential metabolic organ, and its metabolic function is controlled by insulin and other metabolic hormones. Glucose is converted into pyruvate through glycolysis in the cytoplasm, and pyruvate is subsequently oxidized in the mitochondria to generate ATP through the TCA cycle and oxidative phosphorylation. In the fed state, glycolytic products are used to synthesize fatty acids through de novo lipogenesis. Long-chain fatty acids are incorporated into triacylglycerol, phospholipids, and/or cholesterol esters in hepatocytes. These complex lipids are stored in lipid droplets and membrane structures, or secreted into the circulation as very low-density lipoprotein particles. In the fasted state, the liver secretes glucose through both glycogenolysis and gluconeogenesis. During pronged fasting, hepatic gluconeogenesis is the primary source for endogenous glucose production. Fasting also promotes lipolysis in adipose tissue, resulting in release of nonesterified fatty acids which are converted into ketone bodies in hepatic mitochondria though β-oxidation and ketogenesis. Ketone bodies provide a metabolic fuel for extrahepatic tissues. Liver energy metabolism is tightly regulated by neuronal and hormonal signals. The sympathetic system stimulates, whereas the parasympathetic system suppresses, hepatic gluconeogenesis. Insulin stimulates glycolysis and lipogenesis but suppresses gluconeogenesis, and glucagon counteracts insulin action. Numerous transcription factors and coactivators, including CREB, FOXO1, ChREBP, SREBP, PGC-1α, and CRTC2, control the expression of the enzymes which catalyze key steps of metabolic pathways, thus controlling liver energy metabolism. Aberrant energy metabolism in the liver promotes insulin resistance, diabetes, and nonalcoholic fatty liver diseases.

Energy metabolism in the liver

This report updates the 2020-21 recommendations of the Advisory Committee on Immunization Practices (ACIP) regarding the use of seasonal influenza vaccines in the United States (MMWR Recomm Rep 2020;69[No. RR-8]). Routine annual influenza vaccination is recommended for all persons aged ≥6 months who do not have contraindications. For each recipient, a licensed and age-appropriate vaccine should be used. ACIP makes no preferential recommendation for a specific vaccine when more than one licensed, recommended, and age-appropriate vaccine is available. During the 2021-22 influenza season, the following types of vaccines are expected to be available: inactivated influenza vaccines (IIV4s), recombinant influenza vaccine (RIV4), and live attenuated influenza vaccine (LAIV4).The 2021-22 influenza season is expected to coincide with continued circulation of SARS-CoV-2, the virus that causes COVID-19. Influenza vaccination of persons aged ≥6 months to reduce prevalence of illness caused by influenza will reduce symptoms that might be confused with those of COVID-19. Prevention of and reduction in the severity of influenza illness and reduction of outpatient visits, hospitalizations, and intensive care unit admissions through influenza vaccination also could alleviate stress on the U.S. health care system. Guidance for vaccine planning during the pandemic is available at https://www.cdc.gov/vaccines/pandemic-guidance/index.html. Recommendations for the use of COVID-19 vaccines are available at https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/covid-19.html, and additional clinical guidance is available at https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vaccines-us.html.Updates described in this report reflect discussions during public meetings of ACIP that were held on October 28, 2020; February 25, 2021; and June 24, 2021. Primary updates to this report include the following six items. First, all seasonal influenza vaccines available in the United States for the 2021-22 season are expected to be quadrivalent. Second, the composition of 2021-22 U.S. influenza vaccines includes updates to the influenza A(H1N1)pdm09 and influenza A(H3N2) components. U.S.-licensed influenza vaccines will contain hemagglutinin derived from an influenza A/Victoria/2570/2019 (H1N1)pdm09-like virus (for egg-based vaccines) or an influenza A/Wisconsin/588/2019 (H1N1)pdm09-like virus (for cell culture-based and recombinant vaccines), an influenza A/Cambodia/e0826360/2020 (H3N2)-like virus, an influenza B/Washington/02/2019 (Victoria lineage)-like virus, and an influenza B/Phuket/3073/2013 (Yamagata lineage)-like virus. Third, the approved age indication for the cell culture-based inactivated influenza vaccine, Flucelvax Quadrivalent (ccIIV4), has been expanded from ages ≥4 years to ages ≥2 years. Fourth, discussion of administration of influenza vaccines with other vaccines includes considerations for coadministration of influenza vaccines and COVID-19 vaccines. Providers should also consult current ACIP COVID-19 vaccine recommendations and CDC guidance concerning coadministration of these vaccines with influenza vaccines. Vaccines that are given at the same time should be administered in separate anatomic sites. Fifth, guidance concerning timing of influenza vaccination now states that vaccination soon after vaccine becomes available can be considered for pregnant women in the third trimester. As previously recommended, children who need 2 doses (children aged 6 months through 8 years who have never received influenza vaccine or who have not previously received a lifetime total of ≥2 doses) should receive their first dose as soon as possible after vaccine becomes available to allow the second dose (which must be administered ≥4 weeks later) to be received by the end of October. For nonpregnant adults, vaccination in July and August should be avoided unless there is concern that later vaccination might not be possible. Sixth, contraindications and precautions to the use of ccIIV4 and RIV4 have been modified, specifically with regard to persons with a history of severe allergic reaction (e.g., anaphylaxis) to an influenza vaccine. A history of a severe allergic reaction to a previous dose of any egg-based IIV, LAIV, or RIV of any valency is a precaution to use of ccIIV4. A history of a severe allergic reaction to a previous dose of any egg-based IIV, ccIIV, or LAIV of any valency is a precaution to use of RIV4. Use of ccIIV4 and RIV4 in such instances should occur in an inpatient or outpatient medical setting under supervision of a provider who can recognize and manage a severe allergic reaction; providers can also consider consulting with an allergist to help identify the vaccine component responsible for the reaction. For ccIIV4, history of a severe allergic reaction (e.g., anaphylaxis) to any ccIIV of any valency or any component of ccIIV4 is a contraindication to future use of ccIIV4. For RIV4, history of a severe allergic reaction (e.g., anaphylaxis) to any RIV of any valency or any component of RIV4 is a contraindication to future use of RIV4. This report focuses on recommendations for the use of vaccines for the prevention and control of seasonal influenza during the 2021-22 influenza season in the United States. A brief summary of the recommendations and a link to the most recent Background Document containing additional information are available at https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/flu.html. These recommendations apply to U.S.-licensed influenza vaccines used according to Food and Drug Administration-licensed indications. Updates and other information are available from CDC's influenza website (https://www.cdc.gov/flu); vaccination and health care providers should check this site periodically for additional information.

/pdf/prevention-and-control-of-seasonal-influenza-with-vaccines-1dg9rw8cby.pdf

Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices - United States, 2020-21 Influenza Season.

The linkage of individuals with obesity and COVID-19 is controversial and lacks systematic reviews. After a systematic search of the Chinese and English language literature on COVID-19, 75 studies were used to conduct a series of meta-analyses on the relationship of individuals with obesity-COVID-19 over the full spectrum from risk to mortality. A systematic review of the mechanistic pathways for COVID-19 and individuals with obesity is presented. Pooled analysis show individuals with obesity were more at risk for COVID-19 positive, >46.0% higher (OR = 1.46; 95% CI, 1.30-1.65; p < 0.0001); for hospitalization, 113% higher (OR = 2.13; 95% CI, 1.74-2.60; p < 0.0001); for ICU admission, 74% higher (OR = 1.74; 95% CI, 1.46-2.08); and for mortality, 48% increase in deaths (OR = 1.48; 95% CI, 1.22-1.80; p < 0.001). Mechanistic pathways for individuals with obesity are presented in depth for factors linked with COVID-19 risk, severity and their potential for diminished therapeutic and prophylactic treatments among these individuals. Individuals with obesity are linked with large significant increases in morbidity and mortality from COVID-19. There are many mechanisms that jointly explain this impact. A major concern is that vaccines will be less effective for the individuals with obesity.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/obr.13128

Individuals with obesity and COVID-19: A global perspective on the epidemiology and biological relationships.

Genetic predisposition to multiple sclerosis (MS) only explains a fraction of the disease risk; lifestyle and environmental factors are key contributors to the risk of MS. Importantly, these nongenetic factors can influence pathogenetic pathways, and some of them can be modified. Besides established MS-associated risk factors - high latitude, female sex, smoking, low vitamin D levels caused by insufficient sun exposure and/or dietary intake, and Epstein-Barr virus (EBV) infection - strong evidence now supports obesity during adolescence as a factor increasing MS risk. Organic solvents and shift work have also been reported to confer increased risk of the disease, whereas factors such as use of nicotine or alcohol, cytomegalovirus infection and a high coffee consumption are associated with a reduced risk. Certain factors - smoking, EBV infection and obesity - interact with HLA risk genes, pointing at a pathogenetic pathway involving adaptive immunity. All of the described risk factors for MS can influence adaptive and/or innate immunity, which is thought to be the main pathway modulated by MS risk alleles. Unlike genetic risk factors, many environmental and lifestyle factors can be modified, with potential for prevention, particularly for people at the greatest risk, such as relatives of individuals with MS. Here, we review recent data on environmental and lifestyle factors, with a focus on gene-environment interactions.

Interactions between genetic, lifestyle and environmental risk factors for multiple sclerosis

Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation in the absence of excess alcohol intake. NAFLD is the most common chronic liver disease, and ongoing research efforts are focused on understanding the underlying pathobiology of hepatic steatosis with the anticipation that these efforts will identify novel therapeutic targets. Under physiological conditions, the low steady-state triglyceride concentrations in the liver are attributable to a precise balance between acquisition by uptake of non-esterified fatty acids from the plasma and by de novo lipogenesis, versus triglyceride disposal by fatty acid oxidation and by the secretion of triglyceride-rich lipoproteins. In NAFLD patients, insulin resistance leads to hepatic steatosis by multiple mechanisms. Greater uptake rates of plasma non-esterified fatty acids are attributable to increased release from an expanded mass of adipose tissue as a consequence of diminished insulin responsiveness. Hyperinsulinemia promotes the transcriptional upregulation of genes that promote de novo lipogenesis in the liver. Increased hepatic lipid accumulation is not offset by fatty acid oxidation or by increased secretion rates of triglyceride-rich lipoproteins. This review discusses the molecular mechanisms by which hepatic triglyceride homeostasis is achieved under normal conditions, as well as the metabolic alterations that occur in the setting of insulin resistance and contribute to the pathogenesis of NAFLD.

/pdf/mechanisms-of-hepatic-triglyceride-accumulation-in-non-218eim3rzb.pdf

Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease

Obesity is an independent risk factor for morbidity and mortality from pandemic influenza H1N1. Influenza is a significant public health threat, killing an estimated 250 000–500 000 people worldwide each year. More than one in ten of the world's adult population is obese and more than two-thirds of the US adult population is overweight or obese. No studies have compared humoral or cellular immune responses to influenza vaccination in healthy weight, overweight and obese populations despite clear public health importance. The study employed a convenience sample to determine the antibody response to the 2009–2010 inactivated trivalent influenza vaccine (TIV) in healthy weight, overweight and obese participants at 1 and 12 months post vaccination. In addition, activation of CD8+ T cells and expression of interferon-γ and granzyme B were measured in influenza-stimulated peripheral blood mononuclear cell (PBMC) cultures. Body mass index (BMI) correlated positively with higher initial fold increase in IgG antibodies detected by enzyme-linked immunosorbent assay to TIV, confirmed by HAI antibody in a subset study. However, 12 months post vaccination, higher BMI was associated with a greater decline in influenza antibody titers. PBMCs challenged ex vivo with vaccine strain virus, demonstrated that obese individuals had decreased CD8+ T-cell activation and decreased expression of functional proteins compared with healthy weight individuals. These results suggest obesity may impair the ability to mount a protective immune response to influenza virus.

/pdf/obesity-is-associated-with-impaired-immune-response-to-2q0ncqkzkp.pdf

Obesity is associated with impaired immune response to influenza vaccination in humans

Liver-specific Loss of Long Chain Acyl-CoA Synthetase-1 Decreases Triacylglycerol Synthesis and β-Oxidation and Alters Phospholipid Fatty Acid Composition

Objective

Obese adults have a greater risk of morbidity and mortality from infection with pandemic H1N1 influenza A virus (pH1N1). The objective of the present study was to elucidate the specific mechanisms by which obesity and overweight impact the cellular immune response to pH1N1.



Design and Methods

Peripheral blood mononuclear cells from healthy weight, overweight, and obese individuals were stimulated ex vivo with live pH1N1 and then markers of activation and function were measured using flow cytometry and cytokine secretion was measured using cytometric bead array assays.



Results

CD4+ and CD8+ T cells from overweight and obese individuals expressed lower levels of CD69, CD28, CD40 ligand, and interleukin-12 receptor, as well as, produced lower levels of interferon-γ and granzyme B, compared with healthy weight individuals, suggesting deficiencies in activation and function are indicated. Dendritic cells from the three groups expressed similar levels of major histocompatibility complex-II, CD40, CD80, and CD86, as well as, produced similar levels of interleukin-12.



Conclusions

The defects in CD4+ and CD8+ T cells may contribute to the increased morbidity and mortality from pH1N1 in obese individuals. These data also provide evidence that both overweight and obesity cause impairments in immune function.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/oby.20383

Heather A. Paich

Papers

Obesity is associated with impaired immune response to influenza vaccination in humans

Liver-specific Loss of Long Chain Acyl-CoA Synthetase-1 Decreases Triacylglycerol Synthesis and β-Oxidation and Alters Phospholipid Fatty Acid Composition

Overweight and obese adult humans have a defective cellular immune response to pandemic H1N1 Influenza a virus

The antibody response to influenza vaccination is not impaired in type 2 diabetics.