Obesity is a metabolic challenge that necessitates working with the body
The Background
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There are currently no ideal treatments for obesity
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While incretins — gut hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) effectively cause weight loss, they also cause loss of lean muscle mass (in addition to fat)
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Due to the lower food intake with incretin drugs, the body also adapts by reducing its metabolic rate and thus attempts to save energy in order to prevent starvation
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Therapeutics that prevent muscle loss as well as the adaptive drop in metabolic rate are needed - agents that directly increase metabolic rate and dissipate excess energy as heat through a natural, physiological process called thermogenesis
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Recent medical studies have demonstrated that humans, like animals, have brown fat cells - a type of cell that has an exceptional capacity to burn calories, wasting energy as heat, and secrete hormones that favor a lean and healthy metabolic state
The Approach
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Some individuals have much more brown fat than others: Lean individuals have more brown fat than obese individuals
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The amount of brown fat can be naturally increased or decreased by environmental factors (e.g., ambient temperature, some hormones)
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Therapeutic drugs can also be used to increase the amount of brown fat and Energesis' drug candidates cause dramatic weight loss from fat only and highly significant increases in metabolic rate (Conversely, treatments that decrease brown fat cause obesity and diabetes.)
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We believe that the development of drugs that increase brown fat and energy dissipation in humans will represent a paradigm shift in the treatment of obesity. All marketed anti-obesity drugs work only by reducing food intake.
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Medications resulting from this innovative approach are expected to produce high-quality weight loss — from fat only, without effects on lean muscle, work synergistically with incretin agents, and induce sustainable body fat loss without the powerful rebound weight gain that plagues current agents like Wegovy/Ozempic and Zepbound
What is "Brown Fat”?
• Brown fat, aka Brown Adipose Tissue (BAT), contains brown adipocytes (brown fat cells)
• Brown adipocytes are cells that share cellular features of both white adipocytes (normal fat cells) and skeletal myocytes (muscle cells), i.e., they can store fat and can “burn” fat extremely quickly
• Brown adipocytes are specialized in dissipating energy (from stored sugars and fats) as heat due to their unique expression of UnCoupling Protein-1 (UCP1)
• Brown adipocytes have two physiological functions:
1. Produce heat to maintain body temperature in a cold environment (and prevent hypothermia)
2. Dissipate excess energy to maintain a healthy body weight/level of body fat (prevent obesity), whereby BAT thus acts as a physiological safety valve to prevent body weight/body fat gain when energy intake is excessive
• BAT is a flexible tissue that can change in size or mass. Human adults are estimated to have 50 - 400 grams of BAT distributed as small packets of brown adipocytes in various locations in the body, with more significant collections in the paravertebral and supraclavicular regions, and well as around the kidneys and adrenal glands
• The amount of BAT in an individual determines the amount of body weight (the so-called “weight setpoint” or “adipostat”), that the body defends: the more BAT mass, the lower the body weight (body fat)
Individual with high body fat (obesity)
Low amount of BAT
Individual with low body fat (lean)
Large amount of BAT
White Adipocytes
White adipocytes
- Single large lipid droplet
- Very few mitochondria
- No UCP1
- Low metabolic rate
Brown Adipocytes
Brown adipocytes
- Many small lipid droplets
- Abundant mitochondria
- High UCP1 expression
- Very high metabolic rate
In Brown Adipocytes, UCP1 acts as a physiological "safety valve" to prevent obesity
Fuel substrates (fats, sugars) are oxidized in mitochondria, organelles which are the so-called “powerhouse” of the cell. The energy from this oxidation generates an electrochemical proton (H+) gradient across the mitochondrial membrane.
Left (above)
In all cell types, protons (H+) return to the mitochondrial matrix through Adenosine Triphosphate (ATP) Synthase, and in doing so generate ATP, the energy currency of the cell. ATP is used for all cellular work.
In the case of excessive ATP supply however (e.g., when food intake is excessive), ATP is used to make fats, which are then stored as body fat (in white adipocytes or “white fat”).
Right
In brown adipocytes, however, the expression of a protein known as UnCoupling Protein-1 (UCP1) allows some of the protons to return to the mitochondrial matrix by bypassing ATP synthase. In this way, energy is dissipated as heat instead of being stored as ATP.
UCP1 therefore dissipates excess energy as heat instead of accumulating the energy as body fat and leading to obesity.
Increasing the amount of brown fat to cure obesity
At Energesis we are not aiming to treat obesity by causing a decrease in food intake, as occurs with the appetite-suppressing GLP-1 agonists and older weight loss drugs. Any approach that reduces caloric intake leads to a physiologic adaptation whereby the body reduces its resting metabolic rate (energy expenditure), in an effort to fight the resulting loss of body fat. This metabolic adaptation is responsible for the well-known “rebound” or “yo-yo” effect seen with weight loss due to food restriction (either medication-induced or dieting-induced). Upon weight loss induced by food restriction, the body will -- at some point, regain weight to return to its initial level of body fat (if not even higher).
The only way to achieve long-term, sustainable weight loss is to increase an individual’s metabolic rate, and the only safe way to accomplish this — that we are aware of — is to restore the amount of brown fat in obese individuals back to a normal, healthy level.