What enzyme is responsible for body fat loss in me?

Enzymes Responsible for Body Fat Loss

Lipoprotein lipase (LPL) and hormone-sensitive lipase (HSL) are the primary enzymes responsible for breaking down stored body fat, with adipose triglyceride lipase (ATGL) also playing a crucial role in initiating triglyceride hydrolysis during basal lipolysis. 1, 2

Primary Fat-Mobilizing Enzymes

Lipoprotein Lipase (LPL)

• LPL is the rate-limiting enzyme for uptake and storage of lipoprotein triglyceride in adipose tissue, controlling how dietary fats are deposited 3, 1
• Paradoxically, adipose tissue LPL activity increases after weight loss and remains elevated during weight maintenance, which may explain why maintaining weight loss is difficult 3
• In obese individuals who lost weight and stabilized at reduced weight for 4-28 months, LPL activity was further elevated compared to baseline, potentially acting as a counterregulatory mechanism to restore original body weight 3
• The tissue-specific expression pattern of LPL determines fatty acid partitioning: decreased LPL in adipose tissue and increased activity in muscle are both associated with resistance to obesity 1

Hormone-Sensitive Lipase (HSL)

• HSL is the major lipase for catecholamine-stimulated lipolysis, breaking down stored triglycerides in fat cells when activated by stress hormones like epinephrine 2
• Weight loss through very-low-calorie diets results in enhanced HSL activity, though the increase is modest 4
• HSL translocates to lipid droplets when activated, where it accesses stored triglycerides after reorganization of the droplet coating by perilipins 2

Adipose Triglyceride Lipase (ATGL)

• ATGL mediates the initial hydrolysis of triglycerides during basal (unstimulated) lipolysis, representing the first step in fat breakdown 2
• ATGL deficiency in humans causes severe fat accumulation in skeletal muscle, viscera, and pancreas, though surprisingly has minor impact on whole-body insulin sensitivity 5
• The enzyme works in conjunction with HSL, with ATGL initiating triglyceride breakdown and HSL completing the process 2, 5

Lipolytic Regulation Pathways

Stimulatory Mechanisms

• Catecholamines (epinephrine, norepinephrine) stimulate lipolysis through β-adrenoceptors while simultaneously inhibiting it through α2-adrenoceptors 2
• Natriuretic peptides activate a separate lipolytic pathway through cGMP-dependent mechanisms in human fat cells 2
• The balance between these stimulatory and inhibitory signals determines net fat breakdown rates 2

Inhibitory Mechanisms

• Insulin exerts potent antilipolytic effects, suppressing fat breakdown during fed states 2, 4
• Nicotinic acid (niacin) inhibits lipolysis through specific receptors and is used clinically as a hypolipidemic drug 2
• Adrenomedullin, produced by adipocytes themselves, inhibits lipolysis through nitric oxide-mediated mechanisms 2

Clinical Implications for Weight Loss

The Weight Loss Paradox

• After weight loss, elevated adipose tissue LPL activity persists and may predispose to weight regain by enhancing the capacity to store dietary fat 3
• In subjects who lost weight and then regained it, LPL activity increased after weight loss and returned toward baseline with weight regain, suggesting the enzyme acts as a "set point" defender 3
• This enzymatic adaptation represents a biological mechanism resisting sustained weight reduction 3

Metabolic Consequences

• The partitioning of fatty acids between tissues (controlled by tissue-specific LPL expression) has major metabolic consequences beyond simple fat storage 1
• Decreased LPL in adipose tissue combined with increased muscle LPL activity creates resistance to obesity by redirecting fatty acids toward oxidation rather than storage 1

Important Caveats

• Growth hormone treatment significantly reduces adipose tissue LPL activity (by 65%) but does not enhance fat loss beyond caloric restriction alone, indicating LPL inhibition alone is insufficient for additional weight loss 4
• The lipolytic response to catecholamines is impaired in ATGL deficiency, though basal lipolysis rates remain normal, suggesting compensatory mechanisms exist 5
• Targeting these enzymes pharmacologically remains challenging, as chronic lipolysis stimulation must be coupled with fatty acid oxidation to avoid lipotoxicity 2