Adipose and Lipids

Question 1

Hormones involved in systemic effects of obesity (5)

Answer 1

Leptin → reduces appetite, stimulates insulin release. Produced by adipose tissue, concentration is proportional to fat mass and decreases with fasting. Increases with obesity
Possible that with obesity there is resistance to higher leptin concentrations as the anorexigenic effects do not occur.
→ increases metabolic rate, upregulates HPA axis, down regulates thyroid axis and sex hormones.
→ exhibits pro-inflammatory effects, similar structure to IL 6
→ prothrombotic
→ may increase cartilage degradation by increasing expression of MMPs and proteolytic enzymes.

Adiponectin → increases B-oxidation of fatty acids → reduces TGs and improves insulin sensitivity increasing glucose uptake.
→ acts centrally to increase appetite (reciprocal to leptin)
→ improves insulin sensitivity in peripheral tissues
→ anti-inflammatory
Decreases with obesity (paradoxical) due to increases in TNFa and IL6

RAAS → adipose is a source of angiotensinogen, and can activate RAAS → increased AngII and aldosterone
→ role in CKD and CHF not completely understood and paradoxically seems obesity is protective in these diseases.
Betatrophin → from liver and adipose it stimulates glycogen synthesis and inhibits gluconeogenesis. Inhibits muscle lipoprotein lipase but enhances adipose LPL

Visfatin→ produced by various tissues including adipose. Pro inflammatory but also insulin sensitizing.
→ binds to tissues and stimulates use of glucose by adipocytes, also suppressing glucose release from liver cells.

Question 2

Major systemic effects of obesity

Answer 2

Pro inflammatory

Insulin resistance

Carcinogenesis

RAAS activation - renal, cardiac and hypertensive issues

Question 3

Definitions of cachexia and sarcopenia.
Pathogenesis

Answer 3

CACHEXIA
Loss of lean body mass occurring secondary to systemic disease: CHF, CKD, DM respiratory disease, cancer. Can occur concurrently with sarcopenia due to aging.
SARCOPENIA
Loss of lean body mass, as for cachexia, but occurs with aging and not with systemic disease. Often accompanied by increase in fat mass → no net change in weight. Caused by reduced activity, inflammatory cytokines, decreased GH and testosterone, insulin resistance and decreased protein synthesis.

Inflammatory mediators → use of protein as the primary energy source over fats → deleterious effects on strength, immune function, wound healing and survival

Question 4

Effects of obesity on other hormons

Answer 4

insulin resistance

increased IGF1 - important for carcinogenesis

Reduced ghrelin - appetite stimulant

GLP 1 - reduced in obesity

Pancreatic peptide (suppresses gastric emptying, inhibits enzyme secretion, suppresses appetite) - decreased in obesity

Question 5

MAnagement of Cachexia

Answer 5

Decreased energy intake - common with systemic disease, reflects and imbalance in orexigenic and anorexigenic signals.
→ appetite stimulation (capromelin, mirtazepine)
→ remove physical factors such as pain that are reducing intake
→ address environmental factors affecting appetite
→ warm the food (cats)
→ feed smaller but more frequent meals

Nutrition: enhance anabolic effect (promote protein synthesis); reduce muscle loss and use an appropriate substrate.
→ ENSURE DIET IS NUTRITIONALLY BALANCED
→ avoid renal or low protein diets in animals where these are not needed (especially in CHF)
Dietary protein restriction does not slow progression of renal disease unless significant proteinuria is present and should be avoided until advanced CKD is present
→ high digestibility, reduced fibre

Omega 3 - increased provision may be associated with a number of benefits in cachexia
→ result in generation of less potent inflammatory mediators (eicosanoids) compared to omega 6
→ decrease TNF and IL1 production
→ studies have shown that it reduces muscle loss in CHF and in some dogs even improved appetite

Feeding Tube - early implementation .
Exercise - .

Question 6

diet composition for management of obesity

Answer 6

Diet composition changes:
High protein: lower energy utilization than for fats/carbs
High fibre: may satiate when combined with high protein diets
Fermentable fibre may reduce insulin resistance
L carnitine: reduces hepatocyte fat accumulation and protective against fasting ketosis.

Question 7

Drugs to aid weight loss

Answer 7

Lipase inhibitors (Tetrahydrolipstatin) - inhibits gastric lipase but not other lipases thus reducing absorption of monoglycerides and FFAs
Can cause GI upset or bloating. Requires fat soluble vitamin supplementation

Microsomal Triglyceride Transfer Protein Inhibitors: reduce fat absorption and release factors that inhibit appetite (peptide YY regulates food intake and is release from enterocytes).
Dirlopeptide and mitratapide
Vomiting, diarrhoea, altered liver function.

Question 8

normal lipid packaging and transport

Answer 8

Dietary lipids emulsified by bile acids and hydrolysed by pancreatic lipases → FFAs and monoacylglycerides.
→ absorbed by enterocyte by diffusion and packaged into TGs to form chlymicrons which enter intestinal lymphatics
→ Lipoprotein lipases remove some FAs for use in GIT
–> Remnants to the liver
→ packaged with Apoproteins → VLDL → lipoprotein lipases remove FFAs from this in peripheral tissues → LDL
→ returns to liver and is either used to make bile acids
HDL is made by the liver (from LDL) but also from many tissues → transport cholesterol back to the liver and to steroidogenic tissues.

Question 9

causes of secondary hyperlipidaemia

Answer 9

Endocrine:hypoTH, HAC, DM
Pancreatitis
Obesity
Protein losing nephropathy
Cholestasis
Hepatic insufficiency
Drugs: phenobarbitone, glucocorticoids, Estrogen

Primary Hyperlipidemia
Min Schnauzers TG&raquo_space;> cholesterol (abnormal VLDL and chylomicrons)
Beagle
Shetland Sheepdog cholesterol > TG
Doberman, Rottweiler, Briard

Question 10

Tx of hyperlipidemia and MOA

Answer 10

1) Diet - optimal fat content of diet has not been determined, <25g/1000kcal ME. RC GILF returned cholesterol to normal in all dogs and TGs to <5.5 in all (normal in 30%). Consider also home cooked ultra low fat diets formulated by nutritionist to ensure balanced. Re-evaluate in 3-4 weeks after starting diet.
JVIM 2020 - prospective controlled clinical trial. TG and cholesterol were significantly lower after diet change and fewer classified as hyperlipidemic. Using RC GI low fat diet.

2) Omega 3 - complex MOA alteration of transcription factors and affect the arachidonic acid concentration in plasma lipids (altering PGs, LTs and TXA) → reduced lipogenesis, increased B oxidation and activation of lipoprotein lipase.
AEs rare. Typically higher doses required for lipid lowering

3) Fibrates (fenofibrate, gemfibrozil, bezafibrate)- MOA agonist of peroxisome proliferator-activated receptor a → nuclear transcription factor → suppress FA synthesis, stimulate FA oxidation and lipoprotein lipase
JVIM 2021 - micronised nanocrystal formulation, not all on low fat diet but diets did not change. Effective in lowering lipids in 10 dogs over 9 weeks with dose escalation if not normalised every 3 weeks. No significant AEs reported.
JFMS 2022 - Tx of secondary hyperlipidemia, various underlying endocrine causes.17 cats, 1 got diarrhoea remainder no AEs. Majority of cats normalised lipids. Only short term study. Long term safety not yet determined.

4) Niacin (B3) - more adverse effects

5) Statins - not recommended