metabolic syndrome

Jan O Aaseth, Innlandet Hospital and

Inger-Lise Steffensen Norwegian Institute of Public Health

Disposition

• Obesogenic chemicals and the obesogen hypothesis • an example is TriButylTin =TBT • A wider concept: Metabolism disrupting chemicals (MDC) and the MDC hypothesis

• Metabolic syndrome (MetS) • Animal models for MetS

Sykehuset Innlandet HF

Causes of the increase in obesity • Obesity is caused by an unbalance between energy intake and energy expenditure

• Is affected both by genetic factors plus environmental factors

•Easy access to tasteful, cheap food •More energy-dense food •Large portion sizes and packages •Less physical activity at work, during travels and leisure time

Schematic illustrating the neuroendocrine control of energy balance

Heindel et al., Reprod. Toxicol., x, xx-xx, 2016 (modified from Schwartz et al., Nature, 404, 661-671, 2000.

Genes involved in overweight/obesity

The leptinmelanocortinsignalling pathway Oswal, Yeo. Obes. Rev., 8;293-306:2007

Causes of the ‘obesogenic epidemic’ • Unbalanced energy intake and energy expenditure • • • • • • • •

Microorganisms (infections, gut microbiota) Inflammation Increased age of mothers Lack of sleep Hormones Side-effects of drugs Effects on the fetus and over generations probably via epigenetic mechanisms Environmental contaminants (often endocrine disrupting chemicals (EDC)

McAllister et al., Crit. Rev. Food Sci., 49;868-913:2009

Increased body weight (bw) also in animals

• 12 populations, >20 000 animals, 8 species, both genders • Positive trend for increased bw in all populations • Increased bw also in pets (dogs and cats) • Also increased mean bw in

primates and rodents, experimental animals and wild rodents • Caused by virus or environmental contaminants ? • Also increased bw in

infants Klimentidis et al., Proc. R. Soc. B, 278;1626-1632:2011

Parallel increase in obesity and exposure for environmental contaminants P.F. Baillie-Hamilton (2002): suggested that chemicals have a role in causing obesity, exposure may have damaged the body’s natural weight control mechanisms

The obesogen hypothesis (Grün F. & Blumberg B. (2006): certain chemicals (natural, pharmaceutical or xenobiotic) can promote weight gain and obesity, especially when exposed during gestation

Suspected obesogenic chemicals •Tributylin (TBT)/triphenyltin (TPT) •Bisphenol A (BPA) •Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) •Diethylstilbestrol (DES) •Polychlorinated biphenyls (PCB) •Polybromated diphenylethers (PBDE) •Hexachlorobenzene

•Phthalates •DDT •Medications: anti-psychotics, SSRIs, tricyclic antidepressants, thiazolidinedione anti-diabetic drug

Obesogens are often endocrine disrupting chemicals (EDC) • Endocrine disrupting chemicals (EDC) are environmental contaminants that mimic / change effects of natural hormones • They (EDCs) disturbs hormonal signals in the body, via hormone-receptor-signalling pathways, such as e.g. •sex steroids • retinoic X receptor (RXR)-peroxisome proliferator activated receptors (PPAR) •glucocorticoid receptors (GR) • These effects may be increased if the disturbance occurs during ‘critical windows’ in the fetus or infant

Mechanisms of adipocyte formation and sites of action of metabolism disruptors

Heindel et al., Reprod. Toxicol., x, xx-xx, 2016

Tributyltin (TBT) and other organotin compounds • Are no longer used as antifouling agents on boats, but organotins are still used as fungicide and pesticides, for treatment of wood, in textiles, in industry and to stabilise PVC in water pipes, food packaging/other plastic products • Humans are exposed via food (fish, shellfish a.o.), drinking water and house dust • Both TBT and triphenyltin (TPT) bind with high affinity to two nuclear receptors that are important for adipocyte development: retinoid X receptor (RXR) and peroxisome proliferator activated receptors (PPARγ) both in vitro and in vivo (Grün et al., Mol. Endrocrinol., 20;21412155:2006)

Tributyltin (TBT) In vitro model: TBT promotes adipogenesis in mouse preadipocytes 3T3-L1 via direct binding to RXRα and PPARγ

Grün et al., Mol. Endrocrinol., 20;2141-2155:2006

Tributyltin (TBT) In utero exposure of mice to TBT increases adipose mass in liver, testis and other fat deposits in newborn mice

live r

testis

inguina l adipos e tissue mammar y adipose tissue vehicle (sesame oil)


0.5 mg/kg bw TBT

Tributyltin (TBT) TBT increases adipose mass, but not body weight, in adult mice after exposure in utero


Tributyltin (TBT) Chronic exposure of male mice for TBT induced pancreatic islet cell apoptosis and disrupted glucose homeostasis

Zuo et al., Environ. Sci. Technol., 48;5179-5186:2014

Tributyltin (TBT) - Transgenerational effects

Skinner MK, Mol. Cell. Endocrinol., 398;4-12:2014

Tributyltin (TBT) - Transgenerational effects • C57BL/6J female mice (F0) were exposed to a pharmacologic obesogen (Rosiglitazone) or three doses of TBT (5.42, 54.2 and 542 nM TBT) in utero via drinking water, and the offspring (F1) (exposed in utero) were further bred to yield F2 (exposed as germ cells in F1) and F3 (not exposed to TBT)

• Prenatal TBT increased the weight of most white adipose tissue depots, adipocyte size and number • Prenatal TBT reprogrammed mesenchymal stem cells (MSC) from the bone marrow toward the adipocyte linage at the expense of bone cells in all three generations Chamorro-García et al., Environ. Health Perspect., 121;359-366:2013

Tributyltin (TBT) - Transgenerational effects Prenatal TBT exposure led to hepatic lipid accumulation and upregulated hepatic expression of genes involved in lipid storage/transport, and lipogenesis in all three subsequent generations resembling nonalcoholic fatty liver disease (NAFLD) Chamorro-García et al., Environ. Health Perspect., 121;359-366:2013

Tributyltin (TBT) – Human data • In a prospective Finnish study, the level of TBT in placenta was positively associated (P=0.024) with weight gain in boys in the first 3 months of life, but there were no other significant associations with weight gain at 3-18 months or with ponderal index (PI) (ratio between mass (kg)/height3 (m3)) • These results should be interpreted with caution because obesogenic effects in animals were seen after in utero TBT exposures to doses that were several orders of magnitude higher, and the number of persons was limited in this study (n= 110) Rantakokko et al., Environ. Health, 13;45:2014

A wider concept than just ‘obesogens’ • Chemicals that increase obesity: obesogens • Chemicals that cause or lead to diabetes: diabetogens

• ………. • Chemicals that cause or lead to metabolic diseases: metabolism disrupting chemicals (MDC)

• The metabolism disrupting chemical (MDC) hypothesis postulates that environmental chemicals have the ability to promote metabolic changes that can results in obesity, type II diabetes (T2D) or fatty liver in animals, including humans; and potentially playing important roles in the global epidemics of obesity, T2D and MetS (Heindel et al., 2016)

Regulation of pancreas β cell control of blood glucose and sites of action of metabolism disruptors

Heindel et al., Reprod. Toxicol., x, xx-xx, 2016

Regulation of hepatic lipid metabolism and sites of action of metabolism disruptors

The lipotoxicity hypothesis: overproduction and accumulation of triglycerides in the nonadipose tissues, such as liver, pancreas and Heindel et al., Reprod. Toxicol., x, xx-xx, 2016 muscle

Metabolic syndrome (MetS) Definition by WHO (1999): Either diabetes mellitus, impaired glucose tolerance, impaired fasting glucose or insulin resistance, in addition to at least two of the following: • Blood pressure: ≥140/90 mmHg • Dyslipidemia: triglycerides ≥1.695 mmol/l and HDLcholesterol ≤0.9 mmol/l (males), ≤1.0 mmol/l (females) • Central (abdominal) adiposity with waist:hip ratio >0.9 (males) and >0.85 (females) and/or body mass index (BMI) >30 kg/m2 • Microalbuminuria: urinary albumin excretion ratio ≥20 µg/min or albumin:creatinine ratio ≥30 mg/g

Approaches used to induce MetS in animal models (mostly mice and rats) • Dietary modification • Pros: Suitable for studies of non-genetic lifestyledependent MetS in humans, inexpensive • Cons: Delayed onset of MetS, lengthy diet regimen • Genetic modification • Pros: Severe and spontaneously occurring MetS • Cons: Do not resemble most humans with MetS with intact leptin or leptin receptor genes, costly, • Drug/chemical-induced • Pros: Suitable for studies of drug/chemical-related MetS, inexpensive • Cons: Delayed onset of MetS Wong et al., Nutr. Metab., 13;65:2016.

Thank you for your attention!