The science of weight-loss: what your hormones and brain have to do with it

Weight-loss is something that most people, not just women, will come to see a Nutritionist for. So, I thought I would put down, in one space, some of the science behind hormones and weight loss, what I see in clinic with my clients and why the simple equation of calories in and calories out doesn’t always work.

Defining a set-point

The set point theory suggests that the body has a predetermined, genetically influenced weight range it tries to maintain through various physiological mechanisms. This theory is based on homeostasis, whereby everything your body does is driving towards maintaining a steady internal physical and chemical condition i.e. a steady level of weight.

The hypothalamus is like a master regulator or puppeteer in this management of a set point and overall metabolism of your body. He is involved in regulating temperature, hunger, thirst, sleep and mood to keep your body in a stable, constant state of balance (homeostasis!).

What is a set point exactly? It’s not a rigid or fixed number, but a defended weight range. The brain (hypothalamus) will “push back” when weight deviates (particularly downward) from that range. When weight falls below your set point, for example when you’re on a very low-calorie diet or calorie-restricted diet, this signals to your body that you are effectively in some sort of famine situation. Remember, your hypothalamus can’t differentiate between genuine famine vs. a conscious calorie restricted diet. What happens is the hypothalamus recognizes low calorie input, it turns down metabolism to conserve energy, and it will put out food-seeking behaviour (read – you’ll get hungry!).

Conversely, if you are eating more than what is required, your body will turn up the dimmer switch of basal metabolic function, you may feel energised, more alert, heart is beating faster, all to burn the extra calories. So why doesn’t that work all the time to keep your weight in a ‘normal’ range? The answer to that is multi-factorial and depends on the diet, genetics and epigenetics, and lifestyle.

Our bodies are designed to carry a certain amount of fuel on board to last us in times of famine – makes sense. So, when we spend time in a famine situation (a.k.a. low-calorie diet), your brain will try everything it can to defend that set point (as described above). So once you’ve returned to your set point, your brain will ask your body to hold just a little bit more, in case that famine situation happens again. It’s often referred to as “fat overshoot.”

What makes your set point different from someone else’s?

Your genes matter. Everyone is born with a slightly different set of genes that control appetite, satiety, how efficiently we burn energy, and where we store fat. Some people naturally have higher levels of appetite-stimulating hormones (like ghrelin) or lower sensitivity to satiety signals (like leptin). Inherited differences can predispose one person’s body to defend a higher weight range (say 80 kg) and another’s to stabilize at a lower one (say 60 kg). In fact, up to 70% of someone’s risk of developing obesity is determined by genetics. But, it’s not all doom and gloom, the important nuance here is that you have to have the external environmental factors (like, food, stress, sleep) to “switch on” these obesogenic genes.

Your early life environment also is a factor in how your body determines it’s own set point. Nutrition and stress in the womb and childhood diet influence how these genes are expressed, as referred to above. This is “epigenetics.” Epigenetics refers to chemical tags that sit on top of DNA that turn certain genes on or off without changing the DNA sequence itself. These tags are influenced by diet, stress, sleep, toxins, and even experiences in the womb.

Over time, these small switches can reshape how our metabolism, appetite hormones, and fat-storage genes behave. For example, chronic high-sugar intake, persistent stress, or exposure to obesogenic chemicals can silence genes that help burn fat and activate genes that favour energy storage. Conversely, good sleep, regular exercise, and nutrient-dense whole foods can create an epigenetic environment that supports metabolic flexibility and better leptin and insulin signalling.

Because epigenetic changes can accumulate, and sometimes be passed down to future generations, they help explain why each person’s weight-regulation system is unique and also why two people who started life similarly, can diverge later on.

Hormonal signalling sensitivity is also another significant factor into why one’s set point is different to another. Your hypothalamus constantly reads signals from leptin, insulin, thyroid hormones, and gut peptides. How sensitive your brain is to those signals depends on genetics and past diet.

In a nutshell? Genetics and environmental cues (diet, sleep, stress) all influence how these genes are expressed and therefore how our brain interprets these signals and what it believes our set point should be.

Can we change this set point?

We can’t change our genes or genetic adaptations that occurred in the womb based on the environment of you as a foetus. BUT, we can shift the set point over time using diet and lifestyle factors to better influence the expression of our genes; we’re basically feeding our brain ‘better’ information from its external environment with what to judge our homeostasis level with.

How hormones influence set point and weight

I have already mentioned hormones such as insulin, leptin and thyroid hormones, so it’s about time I defined them and put them into context.

Leptin

Leptin is a hormone that is released by fat cells and signals to our hypothalamus that we are full, stop eating. When we have adequate fat stores, leptin levels rise, which signals to the hypothalamus that we are full, we have enough energy reserves, you can now suppress appetite and boost metabolism. So, how does someone ever get to a point where they carry too many reserves (or fat stores) if this pathway exists? The answer lies in our next hormone, insulin. But first, it is important to mention here the term “leptin resistance.” This is where the brain fails to ‘see’ leptin and continues to boost hunger and food-seeking behaviour. What drives this? Highly processed foods, disrupted circadian rhythms, constant snacking and high insulin.

Insulin

Insulin is a hormone that regulates blood sugar. Think of him as a key that unlocks your cell and pushes glucose into that cell. High blood sugar is very toxic on the body; the effects of dysregulated blood sugars in type I or II diabetes is loss of limbs, organ failure, diabetic comas. So, your body will prioritise managing blood sugars over lots of other functions.

Read more here about the hormonal hierarchy, and why balancing blood sugars is key to hormonal health.

How are leptin and insulin linked? When there are high blood sugars, there is high insulin as well – he’s working hard to push that glucose level down, move it out of the blood and into your liver, muscle or fat cells. The problem is that insulin and leptin share the same chemical signaling pathway to the hypothalamus. So, when there is high insulin, your body doesn’t hear leptin as well = leptin resistance. Remember, your body will prioritise the insulin over the leptin, as it’s more important from a survival perspective to manage the blood sugars than it is to manage the feeling of fullness.

How does this influence fat storage? Constant high insulin caused by frequent eating, highly processed foods and sugar, blunt the signaling clarity of leptin and therefore satiety pathways, making the brain think fat stores are lower than they actually are. So you’re still hungry.

High insulin is a big driver in pushing your set point upwards. Think of insulin as your ‘fat storage’ hormone instead of fat burning; because when insulin is high it signals to the body that energy is abundant so it prioritises storing rather than burning fuel.

Thyroid hormones

T4 is your storage form of thyroid hormone and T3 is your biologically active form of thyroid hormone. These hormones determine how quickly the body burns energy. The hypothalamus controls this via the HPT axis (hypothalamic–pituitary–thyroid):

1.     The hypothalamus releases TRH (thyrotropin-releasing hormone).

2.     TRH stimulates the pituitary to secrete TSH (thyroid-stimulating hormone).

3.     TSH tells the thyroid to release T4 and T3, which increase the metabolic rate in tissues.

When leptin and insulin levels are low (as in fasting, dieting, or starvation), the hypothalamus downregulates this pathway = less TRH = less TSH = less T3. This lowers metabolism to conserve energy, helping the body survive a “famine.” This is part of adaptive thermogenesis, the same mechanism that makes long-term calorie restriction so difficult to maintain. Conversely, when leptin and insulin levels are appropriate and the hypothalamus senses safety, it maintains healthy thyroid output; keeping metabolism active and stable.

Why diets often fail and sometimes backfire

So, we know that we have a ‘set point’ that is a weight range that our body sees as a ‘safe’ space to be. We also know that we can influence this set point, to a degree, based on the food and lifestyle choices we make, over time. We’ve also outlined certain hormones that play a major part in how our body determines our set point.

In the context of all this, why do diets fail and sometimes backfire? The answer lies in the duration of a diet and the external factors surrounding it; the ‘dimmer switch’ analogy that we used above. Diets do work in the short term, calorie restriction will cause weight to reduce, but then after a month or so, your body stabilises at a certain point and gets used to that low calorie intake; the dimmer switch has been turned down, the metabolism slows to conserve energy and after a while your body will turn up the food searching signals, so you get hungry and tired. Then the ‘fat overshoot’ occurs; whereby your body stores a little bit more for the next “famine” that might occur.

And this is exactly how ‘yo-yo’ diets happen, and over the years you’re left wondering why you’re steadily heavier. In fact, research suggests that the more dieting attempts on the body, the more defensive your body becomes and the defended weight range becomes higher. The ‘failure’ is not due to moral weakness or laziness, but due to the biological push back from the set-point machinery of our bodies.

What other factors influence weight loss or gain?

Stress and sleep are two of the most underrated, yet powerful, regulators of your weight set point.

I see it time and time again in clinic: someone comes in feeling “stuck,” frustrated that the scales won’t budge despite eating well or exercising regularly. Often, they don’t even realise how much mental, physical, or emotional stress they’re carrying. Chronic stress keeps the body in a heightened state of alert, raising cortisol (your main stress hormone), which tells the body to conserve energy and store more fat, particularly around the middle. Over time, this constant signal shifts the body’s metabolic settings, driving cravings for quick energy foods and making it harder to burn fat efficiently.

Sleep plays a similar role. When you’re not sleeping well, your body’s hunger and satiety hormones (leptin and ghrelin) become unbalanced. You feel hungrier, crave sugar and refined carbs, and your cells become less sensitive to insulin, meaning your body is more likely to store energy instead of using it. Poor sleep also disrupts the communication between the hypothalamus and thyroid, further slowing metabolism and reinforcing the body’s tendency to defend a higher weight set point.

When stress and sleep are optimised, the body feels safe to let go of stored energy. Hormones begin to communicate properly again, inflammation reduces, and metabolism can recalibrate. In other words, improving sleep and managing stress clears the biological pathway that allows weight loss to occur naturally and sustainably.

So… what can we do about all this?

If you’re one of my clients, this will sound familiar; I’m a broken record on this for a reason. The answer is rarely found in the latest hack or supplement; it’s about coming back to the basics. When we eat mostly whole foods, prioritise sleep, and manage stress, we start to shift the internal environment that determines our weight set point. These are the foundations that make lasting change possible, not just for weight loss, but for long-term health and energy.

There’s no quick fix (even though the market loves to sell them). Some options can help short-term, but if your goal is sustainable, healthy weight loss (the kind that actually stays off) we need to work with your biology, not against it.

So, where do you start? Begin by cutting added sugar, then reduce unnecessary snacks, because every time you eat, your body releases insulin, and that constant insulin response keeps you in “storage mode.” Next, start swapping out ultra-processed foods for real ones, and choose carbohydrates that work with your metabolism, not against it.

But rather than focusing on restriction, I encourage my clients to focus on what to add in — more protein, fibre, colour, hydration, and rest. When you build on nourishment instead of deprivation, your mindset (and your plate) shift naturally.

And while weight is one marker, it’s not the only one that matters. Ask yourself:

• Do you have more energy throughout the day?

• Is your sleep deeper and more consistent?

• Are your joints less stiff, your digestion calmer, your mind clearer?

• Are your blood markers improving?

These are the real signs of progress and they often appear long before the number on the scale moves.

If you’re ready to take a sustainable, supported step toward long-term health (and yes, some weight loss along the way if that’s your goal) I’d love to help guide you there.

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